Excitation-inhibition Balance Research Articles

Heterogeneous GAD65 Expression in Subtypes of GABAergic Neurons Across Layers of the Cerebral Cortex and Hippocampus.

Gamma-aminobutyric acid (GABA), a major inhibitory transmitter in the central nervous system, is synthesized via either of two enzyme isoforms, GAD65 or GAD67. GAD65 is synthesized in the soma but functions at synaptic terminals in an activity-dependent manner, playing a distinct role in excitatory-inhibitory balance. However, the extent to which each GABAergic subtype expresses GAD65 in the resting state remains unclear. In this study, we compared GAD65 expression among six GABAergic subtypes: NPY+, nNOS+, PV+, SOM+, CR+, and CCK+. According to the results, the GABAergic subtypes were classified into two groups per region based on GAD65 expression levels: high-expression (NPY+ and nNOS+) and low-expression groups (PV+, SOM+, CR+, and CCK+) in the cerebral cortex and high-expression (NPY+, nNOS+, and CCK+) and low-expression groups (PV+, SOM+, and CR+) in the hippocampus. Moreover, these expression patterns revealed a distinct laminar distribution in the cerebral cortex and hippocampus. To investigate the extent of GAD65 transport from the soma to synaptic terminals, we examined GAD65 expression in colchicine-treated rats in which GAD65 was synthesized in the soma but not transported to terminals. We found a significant positive correlation in GAD65 expression across subtypes between colchicine-treated and control rats. In summary, each GABAergic subtype exhibits a distinct GAD65 expression pattern across layers of the cerebral cortex and hippocampus. In addition, the level of GAD65 expression in the soma can be used as a proxy for the amount of GAD65 in the cytoplasm. These findings suggest that exploration of the distinct profiles of GAD65 expression among GABAergic subtypes could clarify the roles that GABAergic subtypes play in maintaining the excitatory-inhibitory balance.

State-Dependent Effective Connectivity in Resting-State fMRI.

The human brain at rest exhibits intrinsic dynamics transitioning among the multiple metastable states of the inter-regional functional connectivity. Accordingly, the demand for exploring the state-specific functional connectivity increases for a deeper understanding of mental diseases. Functional connectivity, however, lacks information about the directed causal influences among the brain regions, called effective connectivity. This study presents the dynamic causal modeling (DCM) framework to explore the state-dependent effective connectivity using spectral DCM for the resting-state functional MRI (rsfMRI). We established the sequence of brain states using the hidden Markov model with the multivariate autoregressive coefficients of rsfMRI, summarizing the functional connectivity. We decomposed the state-dependent effective connectivity using a parametric empirical Bayes scheme that models the effective connectivity of consecutive windows with the time course of the discrete states as regressors. We showed the plausibility of the state-dependent effective connectivity analysis in a simulation setting. To test the clinical applicability, we applied the proposed method to characterize the state- and subtype-dependent effective connectivity of the default mode network in children with combined-type attention deficit hyperactivity disorder (ADHD-C) compared with age-matched, typically developed children (TDC). All 88 children were subtyped according to the occupation times (i.e., dwell times) of the three dominant functional connectivity states, independently of clinical diagnosis. The state-dependent effective connectivity differences between ADHD-C and TDC according to the subtypes and those between the subtypes of ADHD-C were expressed mainly in self-inhibition, magnifying the importance of excitation inhibition balance in the subtyping. These findings provide a clear motivation for decomposing the state-dependent dynamic effective connectivity and state-dependent analysis of the directed coupling in exploring mental diseases.

Chronic Stress Induces Coordinated Cortical Microcircuit Cell–Type Transcriptomic Changes Consistent With Altered Information Processing

BackgroundInformation processing in cortical cell microcircuits involves regulation of excitatory pyramidal (PYR) cells by inhibitory somatostatin- (SST), parvalbumin-, and vasoactive intestinal peptide–expressing interneurons. Human postmortem and rodent studies show impaired PYR cell dendritic morphology and decreased SST cell markers in major depressive disorder or after chronic stress. However, knowledge of coordinated changes across microcircuit cell types is virtually absent. MethodsWe investigated the transcriptomic effects of unpredictable chronic mild stress (UCMS) on distinct microcircuit cell types in the medial prefrontal cortex (cingulate regions 24a, 24b, and 32) in mice. C57BL/6 mice, exposed to UCMS or control housing for 5 weeks, were assessed for anxiety- and depressive-like behaviors. Microcircuit cell types were laser microdissected and processed for RNA sequencing. ResultsUCMS induced predicted elevations in behavioral emotionality in mice. DESeq2 analysis revealed unique differentially expressed genes in each cell type after UCMS. Presynaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed downregulated postsynaptic gene signatures. Across the cortical microcircuit, we observed a shift from a distributed transcriptomic coordination across cell types in control mice toward UCMS-induced increased coordination between PYR, SST, and parvalbumin cells and a hub-like role for PYR cells. Finally, we identified a microcircuit-wide coexpression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviors. ConclusionsThese findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cells regulating the cortical excitation–inhibition balance, suggesting increased coordinated regulation of PYR cells by SST and parvalbumin cells.

Sharp-Wave Ripple Frequency and Interictal Epileptic Discharges Increase in Tandem During Thermal Induction of Seizures in a Mouse Model of Genetic Epilepsy.

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)—interneuron dependent compound brain rhythms essential for spatial learning and memory—are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation–inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event.

State transitions through inhibitory interneurons in a cortical network model.

Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.

Memory recall involves a transient break in excitatory-inhibitory balance.

The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism.

26.3 Cell-Type–Specific Type 1 Cannabinoid Receptor Distribution Across the Human and Nonhuman Primate Cortex

Alterations in the type-1 cannabinoid (CB1) receptor are implicated in various mental health disorders. CB1 participates in both depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE), suggesting CB1's involvement in both inhibitory and excitatory circuits. However, previous studies describing the distribution of CB1 in human and nonhuman primate cortex utilized antibodies that preferentially target CB1 at inhibitory boutons. Given CB1’s role in both DSI and DSE, understanding cell type–specific CB1 distribution may increase our insight into its regulation of excitatory-inhibitory balance. Here, we investigate CB1 distribution in both inhibitory and excitatory boutons using quantitative fluorescent microscopy. Coronal sections containing dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) from adult male macaques and humans are labeled with antibodies for CB1 (validated to target both excitatory and inhibitory boutons), the vesicular glutamate transporter 1 (VGLUT1; labeling intracortical excitatory boutons), and the vesicular GABA transporter (VGAT; labeling intracortical inhibitory boutons). Samples are imaged to visualize protein expression patterns within cortical regions and layers (10 imaged sites per layer for each brain region of each subject). Fluorescent intensities of CB1 label within boutons of each type are compared using multifactorial ANOVA. CB1 co-expression with both VGLUT1 and VGAT are visualized in axons and boutons in all brain regions of both nonhuman primate and human samples. CB1 fluorescent intensity is lower in excitatory boutons compared to inhibitory boutons across all areas (p < 0.01) and exhibits distinct patterns within each brain region and cortical layer. Previous studies describing the distribution of CB1 in human and nonhuman primate cortex utilized antibodies preferentially targeting CB1 at inhibitory boutons. Using a CB1 antibody that targets both excitatory and inhibitory boutons, we demonstrate distinct cell type–specific regional and laminar distributions of CB1 in the human and nonhuman primate cortex. This may increase our understanding of how CB1 differentially regulates excitatory-inhibitory balance within these areas, and whether cell type–specific CB1 disturbances contribute to the development of psychopathology.

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.

Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder

BackgroundMechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning–based predictions of meaningful clinical improvement. MethodsUsing modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7–15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. ResultsWe observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. ConclusionsBumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex

ObjectiveWhile previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. MethodsUsing individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. ResultsExcitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. ConclusionsThe influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SignificanceThese novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.

Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder.

Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.

Inhibitory interneurons with differential plasticities at their connections tune excitatory–inhibitory balance in the spinal nociceptive system

Networks of the dorsal horn of the spinal cord process nociceptive information from the periphery. In these networks, the excitation-inhibition balance is critical to shape this nociceptive information and to gate it to the brain where it is interpreted as pain. Our aim was to define whether short-term plasticity of inhibitory connections could tune this inhibition-excitation balance by differentially controlling excitatory and inhibitory microcircuits. To this end, we used spinal cord slices from adult mice expressing enhanced green fluorescent protein (eGFP) under the GAD65 promoter and recorded from both eGFP+ (putative inhibitory) and eGFP- (putative excitatory) neurons of lamina II while stimulating single presynaptic GABAergic interneurons at various frequencies. Our results indicate that GABAergic neurons of lamina II simultaneously contact eGFP- and eGFP+ neurons, but these connections display very different frequency-dependent short-term plasticities. Connections onto eGFP- interneurons displayed limited frequency-dependent changes and strong time-dependent summation of inhibitory synaptic currents that was however subjected to a tonic activity-dependent inhibition involving A1 adenosine receptors. By contrast, GABAergic connections onto eGFP+ interneurons expressed pronounced frequency-dependent depression, thus favoring disinhibition at these synapses by a mechanism involving the activation of GABAB autoreceptors at low frequency. Interestingly, the balance favors inhibition at frequencies associated with intense pain, whereas it favors excitation at frequencies associated with low pain. Therefore, these target-specific and frequency-specific plasticities allow to tune the balance between inhibition and disinhibition while processing frequency-coded information from primary afferents. These short-term plasticities and their modulation by A1 and GABAB receptors might represent an interesting target in pain-alleviating strategies.

BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure.

Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing N-methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABAA receptor (GABAAR)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABAAR agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABAAR inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABAAR activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABAAR-α1 and K+/Cl- cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABAAR signaling.NEW & NOTEWORTHY We have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABAA receptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABAA receptor as well as KCC2 transporter immunoreactivity.

Ste20-like Kinase Is Critical for Inhibitory Synapse Maintenance and Its Deficiency Confers a Developmental Dendritopathy

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output. The regulatory mechanisms governing the development of dendrites, however, are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. However, its function in neurons is unknown. We show that, during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ third-order dendrites both in male and in female mice. Moreover, we demonstrate that SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown caused a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, whereas excitatory neurotransmission was unaffected. Finally, we show that this mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations revealed significant loss of SLK expression. Overall, the present data identify SLK as a key regulator of both dendritic complexity during development and inhibitory synapse maintenance.SIGNIFICANCE STATEMENT We show that dysmorphic neurons of human epileptogenic brain lesions have decreased levels of the Ste20-like kinase (SLK). Decreasing SLK expression in mouse neurons revealed that SLK has essential functions in forming the neuronal dendritic tree and in maintaining inhibitory connections with neighboring neurons.

Exercise Restores The Excitation-inhibition Balance In Vta Dopamine Neurons Disrupted By Nicotine Addiction

PURPOSE: The imbalance between excitation and inhibition has been implicated in a variety of neurological disorders including addiction. This study aimed to investigate whether repeated nicotine exposure in vivo altered the excitation-inhibition (E/I) balance of dopamine neurons in the ventral tegmental area (VTA), and if so, whether exercise affects nicotine-induced changes in the E/I balance. METHODS: 2 months old C57BL/6 J mice were randomly divided into sedentary saline group (SS), sedentary nicotine group (SN), exercise saline group (ES) and exercise nicotine group (EN). ES and EN mice were introduced to a treadmill running paradigm (12 m/min for 10 min and 15 m/min for 50 min, 60 min/d, 5 d/w, 8 weeks). The conditioned place preference (CPP) paradigm was used to examine nicotine addiction related behavior. SN and EN mice were given an intraperitoneal injection of nicotine (0.5 mg/kg) while SS and ES mice were given an injection of saline. Patch clamp was used to investigate the excitatory and inhibitory synaptic transmission and E/I ratio in VTA dopamine neurons. RESULTS: Exercise decreased repeated nicotine exposure in vivo induced CPP expression (SS, -27.58 ± 29.72; SN, 123.96 ± 9.74; SE, -21.82 ± 17.23; NE, 65.14 ± 6.58; SS vs. SN, p < 0.001; SN vs. EN, p < 0.001). Exercise restored the reduction of GABAergic inhibition induced by nicotine CPP (IPSC PPR after nicotine acute exposure, SS, 0.53 ± 0.05; SN, 1.23 ± 0.13; SE, 0.71 ± 0.04; NE, 0.81 ± 0.03; SS vs. SN, p < 0.001; SN vs. EN, p < 0.01). Exercise decreases the enhancement of AMPA/NMDA ratio induced by nicotine CPP (SS, 0.58 ± 0.08; SN, 0.96 ± 0.10; SE, 0.62 ± 0.09; NE, 0.59 ± 0.07; SS vs. SN, p < 0.01; SN vs. EN, p < 0.01). Nicotine CPP alters the E/I balance in VTA dopamine neurons, which is reversed by exercise (E/I ratio, SS, 0.74 ± 0.16; SN, 2.09 ± 0.27; SE, 0.86 ± 0.15; NE, 0.96 ± 0.26; SS vs. SN, p < 0.001; SN vs. EN, p < 0.01). CONCLUSIONS: Repeated nicotine exposure in vivo shifts the balance of excitatory and inhibitory synaptic transmission in VTA dopamine neurons. Exercise restores nicotine addiction by reestablishing the balance between excitation and inhibition. Supported by the China Postdoctoral Science Foundation (2018 M641260, 2019 T120067) and the Chinese Universities Scientific Fund (BSU2020038).

Deletion of ErbB4 Disrupts Synaptic Transmission and Long-Term Potentiation of Thalamic Input to Amygdalar Medial Paracapsular Intercalated Cells

Identification of candidate risk genes and alteration in the expression of proteins involved in regulating inhibitory neuron function in various psychiatric disorders, support the notion that GABAergic neuron dysfunction plays an important role in disease etiology. Genetic variations in neuregulin and its receptor kinase ErbB4, expressed exclusively by GABAergic neurons in the CNS, have been linked with schizophrenia. In the amygdala, ErbB4 is highly expressed in GABAergic intercalated cell clusters (ITCs), which play a critical role in amygdala-dependent behaviors. It is however unknown whether ErbB4 deletion from ITCs affects their synaptic properties and function in amygdala circuitry. Here, we examined the impact of ErbB4 deletion on inhibitory and excitatory circuits recruiting medial paracapsular ITCs (mpITCs) using electrophysiological techniques. Ablation of ErbB4 in mpITCs suppressed NMDA receptor-mediated synaptic transmission at thalamo-mpITC synapses and enhanced thalamic driven GABAergic transmission onto mpITCs. Furthermore, long-term potentiation (LTP) at thalamo-mpITC synapses was compromised in ErbB4 mutant mice, indicating that ErbB4 activity is critical for LTP at these synapses. Together, our findings suggest that ErbB4 deletion from mpITCs disrupts excitation-inhibition balance and learning mechanisms in amygdala circuits.

Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity

Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

Effect of acute alcohol intoxication on scale-free neural activity in the lateral septum in rats

Electrophysiological recordings of brain activity show both oscillatory dynamics that typically are analyzed in the time-frequency domain to describe brain oscillatory phenomena and scale-free arrhythmic activity defined as neural noise. Recent studies consider this arrhythmic fractal dynamics of neural noise as a sensitive biomarker of a number of cognitive processes, activity of neurotransmitter systems, changes that accompany neurodegenerative and psychiatric disorders including alcohol use disorder. We tested the changes in neural noise induced by acute alcohol intoxication in the lateral septum for the entire spectrum (1–200 Hz) of local field potential signal and for frequency specific ranges (delta, theta, beta, gamma and epsilon bands). Five male Wistar rats were implanted with intracranial electrodes and local field potential signal was measured for baseline activity and activity induced by acute ethanol intoxication (2 g/kg). Change in neural noise dynamics was assessed as a change in the slope of linear regression fit of power spectral density curves in double logarithmic scale. In our study alcohol resulted in lower incline of scale-free activity in the lateral septum for high frequency range and for the whole spectrum, which is interpreted generally as increase in neural noise and change in neuronal processing in a more stochastic way initiated by the acute alcohol intoxication. At the same time, we observed decrease in neural noise for low frequency range. The observed changes may be related to the shift of the excitatory-inhibitory balance towards inhibition and changes in neurotransmission mostly in the GABAergic system. Scale-free activity was sensitive in the conditions of acute alcohol intoxication, therefore to understand its role in alcohol use disorder we need more data and studies on the underlying processes. Future studies should include simultaneous recordings and analysis of arrhythmic dynamics with the oscillatory and multiunit spiking activity in the lateral septum. It can reveal the contribution of different-scale processes in changes driven by acute alcohol intoxication and clarify the specific electrophysiological mechanisms.

Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications

Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.

Recent advances in the role of excitation-inhibition balance in motor recovery post-stroke.

Stroke affects millions of people worldwide each year, and stroke survivors are often left with motor deficits. Current therapies to improve these functional deficits are limited, making it a priority to better understand the pathophysiology of stroke recovery and find novel adjuvant options. The excitation–inhibition balance undergoes significant changes post-stroke, and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) appears to play an important role in stroke recovery. In this review, we summarise the most recent studies investigating GABAergic inhibition at different stages of stroke. We discuss the proposed role of GABA in counteracting glutamate-mediated excitotoxicity in hyperacute stroke as well as the evidence linking decreased GABAergic inhibition to increased neuronal plasticity in early stroke. Then, we discuss two types of interventions that aim to modulate the excitation–inhibition balance to improve functional outcomes in stroke survivors: non-invasive brain stimulation (NIBS) and pharmacological interventions. Finding the optimal NIBS administration or adjuvant pharmacological therapies would represent an important contribution to the currently scarce therapy options.