Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's dis...Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.展开更多
OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are th...OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d) were posted to 43℃ hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.展开更多
Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracel...Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracellular fluid volume. Gamma-aminobutyric acid (GABA) and Angiotensin (Ang) receptors in the brain are involved with thirst, water intake and balance of body liquid. The present study investigated the interaction between Angiotensinergic and GABAergic systems on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24 h deprivation of water intake. After deprivation the volume of consumed water was measured for 1 h. Administration of Losartan (45 μg/rat), Muscimol (0.1 μg/rat) significantly decreased water intake while, i.c.v. microinjection of Bicuculline (1 μg/rat) significantly increased it as compared to Saline-treated controls. I.C.V. microinjection of Muscimol 15 min after Losartan administration decreased water intake significantly, while, i.c.v. microinjection of Bicuculline 15min after Losartan administration could attenuate increasing effect of Bicuculline on water intake. It is concluded that Angiotensinergic system have interaction with GABAergic system on water intake.展开更多
As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the lea...As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the least controversial therapeutic benefits of acupuncture treatment. To date, the mechanism underlying acupuncture analgesia remains poorly understood. In this review, roles of members of GABAergic neurotransmission system which has long been related to pain perception and modulation, in acupuncture analgesia are discussed.展开更多
Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the de...Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory glutamatergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+channels on summed synaptic excitation when they precede glutamatergic inputs by>15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.展开更多
The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive un...The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.展开更多
Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role ...Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.展开更多
Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrate...Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.展开更多
Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induc...Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induced polarization affects the interneuron response as the interneuron receives NMDA synaptic inputs.Considering the key role of NMDA receptor-mediated supralinear dendritic integration in neuronal computations,we suppose that the applied EFs could functionally modulate interneurons’response via regulating dendritic integration.At first,we build a simplified multi-dendritic circuit model with inhomogeneous extracellular potentials,which characterizes the relationship among EF-induced spatial polarizations,dendritic integration,and somatic output.By performing model-based singular perturbation analysis,it is found that the equilibrium point of fast subsystem can be used to asymptotically depict the subthreshold input–output(sI/O)relationship of dendritic integration.It predicted that EF-induced strong depolarizations on the distal dendrites reduce the dendritic saturation output by reducing driving force of synaptic input,and it shifts the steep change of sI/O curve left by reducing stimulation threshold of triggering NMDA spike.Also,the EF modulation prefers the global dendritic integration with asymmetric scatter distribution of NMDA synapses.Furthermore,we identify the respective contribution of EF-regulated dendritic integration and EF-induced somatic polarization to an action potential generation and find that they have an antagonistic effect on AP generation due to the varied NMDA spike threshold under EF stimulation.展开更多
The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has n...The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.展开更多
Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized acti...Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized activities. Gamma-aminobutyric acid-ergic(GABAergic) pathway is an important inhibitory pathway in retina.In the present study, the effects of GABAergic pathway on the contrast adaptation process of bullfrog RGCs were studied using multi-electrode recording technique. It was found that the application of bicuculline(BIC), a gamma-aminobutyric acid A(GABAA) receptor antagonist, caused a number of changes in the RGCs' response characteristics, including attenuation in adaptation-dependent firing rate decrease and the adaptation-dependent weakening in synchronized activities between adjacent neuron-pairs, whereas intensified the adaptation-dependent RF size shrinkage. These results suggest that GABAAreceptors are involved in the modulation of the firing activity and synchronized activities in contrast adaptation process of the RGCs, whereas the adaptation-related RF property changes involve more complicated mechanisms.展开更多
Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective ser...Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.展开更多
Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitiv...Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-βand tau in patients with Alzheimer’s disease.At present,sleep disorders are considered as a risk factor for,and may be a predictor of,Alzheimer’s disease development.Given that sleep disorders are encountered in other types of dementia and psychiatric conditions,sleep-related biomarkers to predict Alzheimer’s disease need to have high specificity and sensitivity.Here,we summarize the major Alzheimer’s disease-specific sleep changes,including abnormal non-rapid eye movement sleep,sleep fragmentation,and sleep-disordered breathing,and describe their ability to predict the onset of Alzheimer’s disease at its earliest stages.Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer’s disease.This paper therefore explores some potential mechanisms that may contribute to sleep disorders,including dysregulation of the orexinergic,glutamatergic,andγ-aminobutyric acid systems and the circadian rhythm,together with amyloid-βaccumulation.This review could provide a theoretical basis for the development of drugs to treat Alzheimer’s disease based on sleep disorders in future work.展开更多
Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neuroge...Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.展开更多
Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:...Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.展开更多
OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tiv...OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.展开更多
Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availab...Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.展开更多
Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE....Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.展开更多
基金supported by the National Institute on Aging (NIA)National Institutes of Health (NIH)+3 种基金Nos.K99AG065645,R00AG065645R00AG065645-04S1 (to SK)NIH research grants,NINDS,No.R01 NS115834NINDS/NIA,No.R01 NS115834-02S1 (to LG)。
文摘Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.
基金National Natural Science Foundation of China(8163000388).
文摘OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d) were posted to 43℃ hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.
文摘Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracellular fluid volume. Gamma-aminobutyric acid (GABA) and Angiotensin (Ang) receptors in the brain are involved with thirst, water intake and balance of body liquid. The present study investigated the interaction between Angiotensinergic and GABAergic systems on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24 h deprivation of water intake. After deprivation the volume of consumed water was measured for 1 h. Administration of Losartan (45 μg/rat), Muscimol (0.1 μg/rat) significantly decreased water intake while, i.c.v. microinjection of Bicuculline (1 μg/rat) significantly increased it as compared to Saline-treated controls. I.C.V. microinjection of Muscimol 15 min after Losartan administration decreased water intake significantly, while, i.c.v. microinjection of Bicuculline 15min after Losartan administration could attenuate increasing effect of Bicuculline on water intake. It is concluded that Angiotensinergic system have interaction with GABAergic system on water intake.
文摘As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the least controversial therapeutic benefits of acupuncture treatment. To date, the mechanism underlying acupuncture analgesia remains poorly understood. In this review, roles of members of GABAergic neurotransmission system which has long been related to pain perception and modulation, in acupuncture analgesia are discussed.
基金supported by the National Natural Science Foundation of China(32130043 and 32071025)the Interdisciplinary Research Fund of Beijing Normal University,China.
文摘Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory glutamatergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+channels on summed synaptic excitation when they precede glutamatergic inputs by>15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.
基金This work was supported by the National Natural Science Foundation of China(32271056,81671081,and 81701095)University Science and Technology Fund Planning Projects(2022XC002 and 2019XB006).
文摘The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
基金supported by the National Natural Science Foundation of China,No.82171521(to CL)the Special Funds ofTaishan Scholars Project of Shandong Province,No.tsqn202211368(to CL)+2 种基金the Natural Science Foundation of Shandong Province,Nos.ZR2022YQ65(to CL),ZR2021MH073(to CL),ZR2019PH109(to WW)the Projects of Medical and Health Technology Development Program in Shandong Province,China,Nos.202003090720(to DZ),202003070728(to JL),2019 WS329(to DW)the Scientific Research Foundation of Binzhou Medical University,No.BY2018KJ21(to DW)。
文摘Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.
基金supported by the Chongqing Science and Technology CommitteeNatural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。
文摘Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.
基金Project supported by the National Natural Science Foundation of China(Grant No.62171312)the Tianjin Municipal Education Commission Scientific Research Project,China(Grant No.2020KJ114).
文摘Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induced polarization affects the interneuron response as the interneuron receives NMDA synaptic inputs.Considering the key role of NMDA receptor-mediated supralinear dendritic integration in neuronal computations,we suppose that the applied EFs could functionally modulate interneurons’response via regulating dendritic integration.At first,we build a simplified multi-dendritic circuit model with inhomogeneous extracellular potentials,which characterizes the relationship among EF-induced spatial polarizations,dendritic integration,and somatic output.By performing model-based singular perturbation analysis,it is found that the equilibrium point of fast subsystem can be used to asymptotically depict the subthreshold input–output(sI/O)relationship of dendritic integration.It predicted that EF-induced strong depolarizations on the distal dendrites reduce the dendritic saturation output by reducing driving force of synaptic input,and it shifts the steep change of sI/O curve left by reducing stimulation threshold of triggering NMDA spike.Also,the EF modulation prefers the global dendritic integration with asymmetric scatter distribution of NMDA synapses.Furthermore,we identify the respective contribution of EF-regulated dendritic integration and EF-induced somatic polarization to an action potential generation and find that they have an antagonistic effect on AP generation due to the varied NMDA spike threshold under EF stimulation.
基金National Natural ScienceFoundation of China(61890953 and 31871088)the Chinese Academy of Medical Sciences Innovation Fund forMedical Sciences(2019-12M-5-014)the Director Fund of Wuhan National Laboratory for Optoelectronics.
文摘The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.
基金the National Natural Science Foundation of China(No.61375114)
文摘Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized activities. Gamma-aminobutyric acid-ergic(GABAergic) pathway is an important inhibitory pathway in retina.In the present study, the effects of GABAergic pathway on the contrast adaptation process of bullfrog RGCs were studied using multi-electrode recording technique. It was found that the application of bicuculline(BIC), a gamma-aminobutyric acid A(GABAA) receptor antagonist, caused a number of changes in the RGCs' response characteristics, including attenuation in adaptation-dependent firing rate decrease and the adaptation-dependent weakening in synchronized activities between adjacent neuron-pairs, whereas intensified the adaptation-dependent RF size shrinkage. These results suggest that GABAAreceptors are involved in the modulation of the firing activity and synchronized activities in contrast adaptation process of the RGCs, whereas the adaptation-related RF property changes involve more complicated mechanisms.
基金supported by the Max Planck Society to C.W.T.and National Institutes of Health USDHHS(R01-HD065826to M.G.,OD011107 to Harris Lewin)。
文摘Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.
基金This work was funded by the National Natural Science Foundation of China, Nos. 81660151 (to FFH), 81660751 (to SLY).
文摘Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-βand tau in patients with Alzheimer’s disease.At present,sleep disorders are considered as a risk factor for,and may be a predictor of,Alzheimer’s disease development.Given that sleep disorders are encountered in other types of dementia and psychiatric conditions,sleep-related biomarkers to predict Alzheimer’s disease need to have high specificity and sensitivity.Here,we summarize the major Alzheimer’s disease-specific sleep changes,including abnormal non-rapid eye movement sleep,sleep fragmentation,and sleep-disordered breathing,and describe their ability to predict the onset of Alzheimer’s disease at its earliest stages.Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer’s disease.This paper therefore explores some potential mechanisms that may contribute to sleep disorders,including dysregulation of the orexinergic,glutamatergic,andγ-aminobutyric acid systems and the circadian rhythm,together with amyloid-βaccumulation.This review could provide a theoretical basis for the development of drugs to treat Alzheimer’s disease based on sleep disorders in future work.
基金FAPESP-Fundacao de Amparoa Pesquisa do Estado de Sao Paulo,No.2013/12056-0(to GL) and No.2015/02154-0(to CMB)
文摘Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.
基金CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2021-I2M-1-034National Natural Science Foundation of China,Grant/Award Number:31970510Young Elite Scientist Sponsorship Program by CAST,Grant/Award Number:2019QNRC001。
文摘Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.
文摘OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.
基金Supported by funding from the Ophthalmic Research Institute of Australia,the University of Melbourne De Brettville Trustthe Kel and Rosie Day Foundationthe Centre for Eye Research Australia
文摘Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.
基金National Natural Science Foundation of China(913322028122100381603084).
文摘Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.
