GABAergic Inhibitory Circuits Research Articles

Clinical efficacy of low-dose Perampanel correlates with neurophysiological changes in familial adult myoclonus epilepsy 2.

Familial adult myoclonus epilepsy (FAME) management relies on antiseizure medications (ASMs), which inadequately address myoclonus and cortical tremor. This study evaluates Perampanel (PER), an AMPA-receptor antagonist, for treating FAME symptoms. Fifteen FAME2 patients participated in an observational prospective study. They received up to 6 mg daily of PER and underwent Unified-Myoclonus-Rating-Scale (UMRS) before and after treatment. Neurophysiological evaluations, including somatosensory evoked potentials (SEPs) and transcranial magnetic stimulation (TMS), assessed PER's impact on cortical glutamatergic excitatory and GABAergic inhibitory circuits. PER treatment significantly reduced UMRS total scores (p = 0.001) and action-myoclonus subscores (p = 0.002), irrespective of disease duration, age at onset, or testing time (p >0.05). Patients with more severe baseline myoclonus demonstrated significant improvements. Neurophysiological assessments revealed a PER-induced decrease in sensorimotor hyperexcitability, characterized by diminished N33 amplitudes, attenuated glutamatergic facilitation, and enhanced GABAergic inhibition in the motor cortex. In conclusion, low-dose PER is well tolerated and effective in alleviating myoclonus in FAME2 patients, supported by its modulatory effects on glutamatergic and GABAergic neuronal circuits. Plain Language Summary: This study investigated the effects of low-dose perampanel in individuals with Familial Adult Myoclonus Epilepsy2 (FAME2), a hereditary condition characterized by epilepsy and tremors. Perampanel, an antiepileptic drug, blocks AMPA receptors in the brain, reducing excessive neural activity that causes seizures and abnormal movements. The results showed significant symptom improvement, which correlated with changes in brain activity as measured by neurophysiological tests. This study suggests that perampanel helps regulate abnormal brain signals and may help managing FAME2 symptoms.

Neurophysiological assessment of cortical activity in DEPDC5- and NPRL3-related epileptic mTORopathies

BackgroundMutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG).ResultsInhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.ConclusionsThese results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.

The role of inhibitory circuits in hippocampal memory processing.

GABAergic inhibitory circuits play an essential role in coordinating various hippocampal functions. Several decades of work dedicated to a thorough characterization of hippocampal inhibitory populations have highlighted how specific types of interneuron can contribute to network activity. Recent studies have used genetically targeted recordings and peturbations of activity during memory-related behaviours to determine how interneurons that inhibit distinct subcellular domains of principal cells or specialize in principal cell disinhibition may sculpt hippocampal memory. These studies highlight unique contributions of distinct interneuron types to the temporal binding of hippocampal ensembles, synaptic plasticity and the acquisition of spatial and contextual information. Here, we review the current state of knowledge around hippocampal inhibition and memory by discussing the multifaceted roles of populations of inhibitory cells at different stages of hippocampal mnemonic processing.

FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes

Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD). ASD is caused by genetic and environmental factors. Several genes have been associated with syndromic forms of ASD, including FOXG1. However, when and how dysregulation of FOXG1 can result in defects in inhibitory circuit development and ASD-like social impairments is unclear. Here, we show that increased or decreased FoxG1 expression in both excitatory and inhibitory neurons results in ASD-related circuit and social behavior deficits in our mouse models. We observe that the second postnatal week is the critical period when regulation of FoxG1 expression is required to prevent subsequent ASD-like social impairments. Transplantation of GABAergic precursor cells prior to this critical period and reduction in GABAergic tone via Gad2 mutation ameliorates and exacerbates circuit functionality and social behavioral defects, respectively. Our results provide mechanistic insight into the developmental timing of inhibitory circuit formation underlying ASD-like phenotypes in mouse models.

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF.

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain.

Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging.

Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan. Our data showed that while the number and morphological features of I-S3 cells remained unchanged, their firing and synaptic properties were significantly altered in old animals. In particular, the action potential duration and the level of steady-state depolarization were significantly increased in old animals in parallel with a significant decrease in the maximal firing frequency. Reducing the fast-delayed rectifier potassium or transient sodium conductances in I-S3 cell computational models could reproduce the age-related changes in I-S3 cell firing properties. However, experimental data revealed no difference in the activation properties of the Kv3.1 and A-type potassium currents, indicating that transient sodium together with other ion conductances may be responsible for the observed phenomena. Furthermore, I-S3 cells in aged mice received a stronger inhibitory drive due to concomitant increase in the amplitude and frequency of spontaneous inhibitory currents. These age-associated changes in the I-S3 cell properties occurred in parallel with an increased inhibition of their target interneurons and were associated with spatial memory deficits and increased anxiety. Taken together, these data indicate that VIP+/CR+ interneurons responsible for local circuit disinhibition survive during aging but exhibit significantly altered physiological properties, which may result in the increased inhibition of hippocampal interneurons and distorted mnemonic functions.

From Hiring to Firing: Activation of Inhibitory Neurons and Their Recruitment in Behavior.

The investigation of GABAergic inhibitory circuits has substantially expanded over the past few years. The development of new tools and technology has allowed investigators to classify many diverse groups of inhibitory neurons by several delineating factors: these include their connectivity motifs, expression of specific molecular markers, receptor diversity, and ultimately their role in brain function. Despite this progress, however, there is still limited understanding of how GABAergic neurons are recruited by their input and how their activity is modulated by behavioral states. This limitation is primarily due to the fact that studies of GABAergic inhibition are mainly geared toward determining how, once activated, inhibitory circuits regulate the activity of excitatory neurons. In this review article, we will outline recent work investigating the anatomical and physiological properties of inputs that activate cortical GABAergic neurons, and discuss how these inhibitory cells are differentially recruited during behavior.

Vesicular GABA Transporter Is Necessary for Transplant-Induced Critical Period Plasticity in Mouse Visual Cortex.

The maturation of GABAergic inhibitory circuits is necessary for the onset of the critical period for ocular dominance plasticity (ODP) in the postnatal visual cortex (Hensch, 2005; Espinosa and Stryker, 2012). When it is deficient, the critical period does not start. When inhibitory maturation or signaling is precocious, it induces a precocious critical period. Heterochronic transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) can induce a second period of functional plasticity in the visual cortex (Southwell et al., 2010). Although the timing of MGE transplantation-induced plasticity is dictated by the maturation of the transplanted cells, its mechanisms remain largely unknown. Here, we sought to test the effect of blocking vesicular GABA loading and subsequent release by transplanted interneurons on the ability to migrate, integrate, and induce plasticity in the host circuitry. We show that MGE cells taken from male and female donors that lack vesicular GABA transporter (Vgat) expression disperse and differentiate into somatostatin- and parvalbumin-expressing interneurons upon heterochronic transplantation in the postnatal mouse cortex. Although transplanted Vgat mutant interneurons come to express mature interneuron markers and display electrophysiological properties similar to those of control cells, their morphology is significantly more complex. Significantly, Vgat mutant MGE transplants fail to induce ODP, demonstrating the pivotal role of vesicular GABAergic transmission for MGE transplantation-induced plasticity in the postnatal mouse visual cortex.SIGNIFICANCE STATEMENT Embryonic inhibitory neurons thrive when transplanted into postnatal brains, migrating and differentiating in the host as they would have done if left in the donor. Once integrated into the host, these new neurons can have profound effects. For example, in the visual cortex, such neurons induce a second critical period of activity-dependent plasticity when they reach the appropriate stage of development. The cellular mechanism by which these transplanted GABAergic interneurons induce plasticity is unknown. Here, we show that transplanted interneurons that are unable to fill synaptic vesicles with GABA migrate and integrate into the host circuit, but they do not induce a second period of plasticity. These data suggest a role for the vesicular GABA transporter in transplantation-mediated plasticity.

O-1-24. Cortical silent period during force control task

We investigated whether transcranial magnetic stimulation (TMS)-induced cortical silent period (cSP), which reflects activation of the GABAergic inhibitory neural circuit in the primary motor cortex (M1), was modulated with dependency on actual output force and corticospinal excitability. Eleven healthy participants were asked to control the force of abduction of the right index finger to 10–100% of the maximum voluntary contraction. TMS was delivered to the left M1 during the task. The results showed that actual output force level, background electromyography activity (bEMG) and area of motor evoked potential (aMEP) in the right first dorsal interosseous muscle gradually increased with increasing target force level while cSP gradually decreased with increasing target force level. There were also significant negative correlations between cSP and actual output of force level, cSP and bEMG, and cSP and aMEP. These findings indicate that activation of GABAergic inhibitory neural circuits in M1 decreases in response to increased force output, mediated via increased corticospinal and motoneuron excitability.

Chronic GABAergic blockade in the spinal cord in vivo induces motor alterations and neurodegeneration

Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.

Gq/5-HT 2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice.

Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment.

Working memory functions supported by the prefrontal cortex decline in normal aging. Disruption of corticolimbic GABAergic inhibitory circuits can impair working memory in young subjects; however, relatively little is known regarding how aging impacts prefrontal cortical GABAergic signaling and whether such changes contribute to cognitive deficits. The current study used a rat model to evaluate the effects of aging on expression of prefrontal GABAergic synaptic proteins in relation to working memory decline, and to test whether pharmacological manipulations of prefrontal GABAergic signaling can improve working memory abilities in aged subjects. Results indicate that in aged medial prefrontal cortex (mPFC), expression of the vesicular GABA transporter VGAT was unchanged; however, there was a significant increase in expression of the GABA synthesizing enzyme GAD67, and a significant decrease in the primary neuronal GABA transporter GAT-1 and in both subunits of the GABA(B) receptor (GABA(B)R). Expression of VGAT, GAD67, and GAT-1 was not associated with working memory ability. In contrast, among aged rats, GABA(B)R expression was significantly and negatively associated with working memory performance, such that lower GABA(B)R expression predicted better working memory. Subsequent experiments showed that systemic administration of a GABA(B)R antagonist, CGP55845, dose-dependently enhanced working memory in aged rats. This enhancing effect of systemic CGP55845 was reproduced by direct intra-mPFC administration. Together, these data suggest that age-related dysregulation of GABAergic signaling in prefrontal cortex may play a causal role in impaired working memory and that targeting GABA(B)Rs may provide therapeutic benefit for age-related impairments in executive functions.

P 85. Resistance to perturbance by anodal tDCS indicates diminished plasticity of GABAergic intracortical inhibition in old age

Question GABAergic inhibitory circuits are changed as a function of age marked by a prevailing level of disinhibition during resting-state and deficient event-related modulatory capacity, potential mechanisms underlying age-related speed and dexterity deficits. The driving question for the present work was whether anodal transcranial direct current stimulation (atDCS) can influence age-related deficiency of inhibition and “open a window” for event-related modulatory capacity within the intracortical inhibitory network. Furthermore, if intracortical inhibition is to be influenced by atDCS, do direction and amount of the effect correlate with stimulation-induced changes in dexterous motor behaviour? Methods N = 20 healthy right-handed participants (N = 10 young 25.2 ± 1.6 years, range 23–28, 5 female, N = 10 old 73.6 ± 7.5 years, range 65–83, 6 female) volunteered in a double-blind cross-over design. Assessment of short-interval intracortical inhibition (SICI), dexterous hand function, attention and fatigue was performed before, immediately, 45, and 90 min (P, P45, P90) after atDCS (1 mA, 20 min.) or sham stimulation. Dexterous hand function was evaluated with solitary index finger tapping (1FT), alternating index and little finger tapping (2FT), simple reaction time task (SRT), and choice-reaction time task (CRT). Results Our main finding was that resting-state intacortical inhibition was significantly diminished after a single session of 20 min atDCS exclusively in the young but not in old participants (TIME X STIMULATION X GROUP (F (3, 2408) = 8.345, p .9). No atDCS stimulation-effect was observed for event-related SICI modulation, neither in young nor in old. The effect of atDCS on motor behaviour differed among age groups and was dependent on the character of the task performed: While the young showed a similar temporal pattern of performance irrespective of stimulation condition, old subjects tended to improve in SRT and 2FT but showed a significant decline in performance speed in CRT accompanied by a marked improvement in CRT error rate under atDCS. Stimulation-induced release of inhibition was associated with faster performance in SRT after atDCS in the old subgroup (R = −.71, p Conclusions Performance improvements with atDCS in old age cannot be explained solely by changes to intracortical inhibition mediated by GABAergic inhibitory interneurons. When prevailing disinhibition dominates resting-state, no perturbation as seen in young is achieved with atDCS. Event-related modulation of intracortical inhibition, i.e. rapid release of inhibition, seems to follow a hard-coded process, which cannot be influenced by atDCS.

A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo

Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.

Research progress on barrel cortex and its plasticity

Synaptic plasticity of barrel cortex is one of the most widely studied topics in neuroscience in recent years. The primary somatosensory cortex of the rodent has a good topology character,which provides an ideal experimental model for plasticity study. This system displays very strong experience-dependent plasticity both during development and in adulthood. The changes of sensory cortex's neural circuit can induce experience-dependent plasticity. In the synaptic level,thalamocortical synapse is considered to be the main location of plasticity. In the circuit level,both synapses from layer 4 to layer 2/3 and those within layer 2/3 are also the necessary parts of achieving synaptic plasticity in primary somatosensory cortex. The GABAergic inhibitory circuit may be involved in this plasticity of S1, but the exact mechanism remains unknown.

Laminar-Specific Maturation of GABAergic Transmission and Susceptibility to Visual Deprivation Are Related to Endocannabinoid Sensitivity in Mouse Visual Cortex

The developmental period when neuronal responses are modified by visual experience is reported to start and end earlier in layer 4 than in layer 2/3 of the visual cortex, and the maturation of GABAergic inhibitory circuits is suggested to determine the timing of this period. Here, we examine whether the laminar difference in such timing corresponds to a difference in the time course of the functional maturation of GABAergic synaptic transmission to star pyramidal and pyramidal cells in layers 4 and 2/3, respectively, of the mouse visual cortex and whether the development of the strength of GABAergic transmission is affected by visual deprivation in a laminar-specific manner. Our analysis of developmental changes in inhibitory postsynaptic currents of star pyramidal and pyramidal cells evoked by electrical stimulation of afferents or action potentials of fast-spiking GABAergic neurons revealed that there was a sequential maturation of GABAergic function from layers 4 to 2/3. The maturation of inhibition in layer 4 occurred at postnatal week 3, which preceded by 1 week that of layer 2/3. Visual deprivation by dark rearing arrested the functional development of GABAergic transmission in layer 2/3, whereas dark rearing was not so effective in layer 4. GABAergic synapses in layer 2/3 were sensitive to an agonist for cannabinoid type 1 receptors and not normally matured in receptor knock-out mice, whereas those in layer 4 were not so. These results suggest laminar-specific maturation of inhibition and susceptibility to visual deprivation, which may be related to the laminar difference in sensitivity to endocannabinoids.

Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala

The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA.

The role of cortical inhibitory circuits in target selection with saccadic eye movements

In work reported last year at this meeting we had shown that subthreshold microstimulation in V1, V2, LIP, FEF and MEF of monkeys can variously produce facilitation, interference, and delays in saccade initiation, thereby identifying some of the essential neural computations carried out in the process of target selection with saccadic eye movements. We now report the effects of local administration of the GABA antagonist bicuculline and the GABA agonist muscimol on this process. Following fixation, monkeys had the free choice of selecting one of two identical targets presented with various temporal asynchronies, with one placed into the receptive or motor field of the neurons treated with the pharmacological agents. Also tested were the brightness, color and shape discrimination abilities at intact and affected sites. Bicuculline produced a high level of facilitation in the choice of the target appearing in the receptive and motor fields of the neurons in the FEF but yielded major interference in V1. Bicuculline also produced deficits in brightness, color and shape discrimination at the injected sites in V1 but not in LIP and the FEF. Muscimol in V1 produced dramatic interference in target selection as well as in visual discrimination whereas in the FEF it produced only moderate interference. Our results suggest that (1) GABAergic inhibitory circuits in V1 play a central role in the analysis of visual stimuli, (2) Signals for the generation of eye movements in V1 appear to be produced not by disinhibition but predominantly by excitation, (3) in the FEF disinhibition is a central process for initiating eye movements and (4) inhibitory circuits in the FEF do not appear to be central for visual analysis.  Received October 16, 2002.

Abnormal response of motor cortex to photic stimulation in idiopathic generalized epilepsy

Intermittent photic stimulation (IPS) shortens the cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) over the primary motor hand area (M1(HAND)). This response is absent in healthy individuals with a photoparoxysmal response (PPR). Here we combined TMS of the M1(HAND) with IPS to examine whether patients with idiopathic generalized epilepsy (IGE) exhibit an abnormal cortical response pattern to IPS. In 13 PPR-positive and 12 PPR-negative patients with IGE and in 13 PPR-negative healthy controls, we used focal TMS to the M1(HAND) to study how cortical excitability is changed by concurrent IPS at 50 Hz. IPS at 50 Hz reduced the duration of the CSP in healthy PPR-negative individuals, whereas IPS had no effect on the CSP in PPR-positive and PPR-negative patients with generalized epilepsy. The failure of IPS to shorten the CSP was independent of antiepileptic medication. Single-pulse or paired-pulse TMS only without concurrent IPS showed a higher motor threshold in PPR-positive patients with epilepsy, presumably caused by antiepileptic medication. No additional differences in cortical excitability were found among groups. Because the CSP is mediated by intracortical GABAergic mechanisms, our results indicate that IGEs are associated with an altered responsiveness of GABAergic inhibitory circuits in the M1(HAND). This electrophysiological trait is independent of photosensitivity. Excitability changes at the cortical or thalamic level may mediate this abnormal cortical response pattern in patients with IGE.

GAD67-Mediated GABA Synthesis and Signaling Regulate Inhibitory Synaptic Innervation in the Visual Cortex

The development of GABAergic inhibitory circuits is shaped by neural activity, but the underlying mechanisms are unclear. Here, we demonstrate a novel function of GABA in regulating GABAergic innervation in the adolescent brain, when GABA is mainly known as an inhibitory transmitter. Conditional knockdown of the rate-limiting synthetic enzyme GAD67 in basket interneurons in adolescent visual cortex resulted in cell autonomous deficits in axon branching, perisomatic synapse formation around pyramidal neurons, and complexity of the innervation fields; the same manipulation had little influence on the subsequent maintenance of perisomatic synapses. These effects of GABA deficiency were rescued by suppressing GABA reuptake and by GABA receptor agonists. Germline knockdown of GAD67 but not GAD65 showed similar deficits, suggesting a specific role of GAD67 in the maturation of perisomatic innervation. Since intracellular GABA levels are modulated by neuronal activity, our results implicate GAD67-mediated GABA synthesis in activity-dependent regulation of inhibitory innervation patterns.