The Role of Parvalbumin Interneurons in Autism Spectrum Disorder.

As an important subtype of GABAergic interneurons, parvalbumin (PV) interneurons play a critical role in regulating cortical circuits and neural networks. Abnormalities in the development or function of PV interneurons have been linked to autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by social and language deficits. In this review, we focus on the abnormalities of PV interneurons in ASD, including quantity and function and discuss the underlying mechanisms of impairments in PV interneurons in the pathology of ASD. Finally, we propose potential therapeutic approaches targeting PV interneurons, such as transplanting MGE progenitor cells and utilizing optogenetic stimulation in the treatment of ASD.

Imbalance in positive and negative acceleration ratio of alpha oscillation in patients with complex regional pain syndrome.

Objectives: To elucidate the functional characteristics of the brain in the presence of chronic pain using electroencephalography (EEG), with a focus on the dynamics of neural excitation and inhibition. Methods: Resting-state EEG was performed in: 17 patients with complex regional pain syndrome (CRPS) who exhibited chronic pain higher than 20 on the visual analogue scale (VAS), 6 patients with reduced CRPS symptoms and chronic pain less than 20 on VAS, and healthy age-matched controls. For the analysis, 50 s of electroencephalogram (EEG) signals were extracted from EEG recordings during wakefulness and rest with eyes closed. The envelope of the alpha frequency band was calculated by examining the positive and negative accelerations of the envelope oscillation, ratio of positive (Ap) to negative (An) accelerations (Ap-An ratio), and mean amplitude of the envelope. Comparisons were made between patients and controls, and correlations between these EEG measures and the subjective pain VAS were evaluated.Significant differences in the value of Ap, An and Ap-An ratio were observed at temporal and central electrodes between patients with pain symptoms and controls. Those with reduced CRPS symptoms exhibited a distinct Ap-An ratio at the majority of electrodes when compared with those exhibiting chronic pain. Conclusions: Distinct patterns in alpha wave envelope dynamics, reflecting excitatory and inhibitory activities, were associated with chronic pain in patients with CRPS. The pain-relieved state of CRPS suggested that a new balance of activities was established. This relationship indicated a potential association between altered alpha oscillation characteristics and the subjective experience of pain. Significance: This study introduces a novel method for analyzing alpha oscillation envelopes, providing new insights into the neural pathophysiology of chronic pain in CRPS patients. This approach has the potential to enhance our understanding of the alterations in brain function that occur under chronic pain conditions.

Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Dysregulation of parvalbumin expression and neurotransmitter imbalance in the auditory cortex of the BTBR mouse model of autism spectrum disorder.

Individuals diagnosed with autism spectrum disorder (ASD) frequently exhibit abnormalities in auditory perception, a phenomenon potentially attributed to alterations in the excitatory and inhibitory cells constituting cortical circuits. However, the exact genetic factors and cell types affected by ASD remain unclear. The present study investigated the balance of excitatory and inhibitory activity in the auditory cortex using BTBR T+ Itpr3tf/J (BTBR) mice, a well-established model for autism research. Our investigation unveiled a reduction in parvalbumin-positive (PV+) neurons within the AC of BTBR mice. Remarkably, in vivo magnetic resonance spectroscopy studies disclosed an elevation in glutamate (Glu) levels alongside a decrement in γ-aminobutyric acid (GABA) levels in this cortical region. Additionally, transcriptomic analysis of the mouse model facilitated the classification of several ASD-associated genes based on their cellular function and pathways. By comparing autism risk genes with RNA transcriptome sequencing data from the ASD mouse model, we identified the recurrent target gene Scn1a and performed validation. Intriguingly, we uncovered the specific expression of Scn1a in cortical inhibitory neurons. These findings hold significant value for understanding the underlying neural mechanisms of abnormal sensory perception in animal models of ASD.

Unveiling the crucial role of betaine: modulation of GABA homeostasis via SLC6A1 transporter (GAT1).

Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling.In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Here we demonstrate that betaine at low concentration modulates the GABA uptake by GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. This modulation occurs through the temporal inhibition of the transporter, wherein prolonged occupancy by betaine impedes the swift transition of the transporter to the inward conformation. Importantly, the modulatory effect of betaine on GAT1 is reversible, as the blocking of GAT1 disappears with increased extracellular GABA. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine has a dual role in GAT1: at mM concentration acts as a slow substrate, and at µM as a temporal blocker of GABA, when it is below its K0.5. Given this unique modulatory characteristic and lack of any harmful side effects, betaine emerges as a promising neuromodulator of the inhibitory pathways improving GABA homeostasis via GAT1, thereby conferring neuroprotection against excitotoxicity.

Posterior cingulate and medial prefrontal excitation-inhibition balance in euthymic bipolar disorder.

BACKGROUND: Persistent cognitive deficits and functional impairments are associated with bipolar disorder (BD), even during the euthymic phase. The dysfunction of default mode network (DMN) is critical for self-referential and emotional mental processes and is implicated in BD. The current study aims to explore the balance of excitatory and inhibitory neurotransmitters, i.e. glutamate and γ-aminobutyric acid (GABA), in hubs of the DMN during the euthymic patients with BD (euBD). METHOD: Thirty-four euBD and 55 healthy controls (HC) were recruited to the study. Using proton magnetic resonance spectroscopy (1H-MRS), glutamate (with PRESS sequence) and GABA levels (with MEGAPRESS sequence) were measured in the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC) and the posterior cingulate gyrus (PCC). Measured concentrations of excitatory glutamate/glutamine (Glx) and inhibitory GABA were used to calculate the excitatory/inhibitory (E/I) ratio. Executive and attentional functions were respectively assessed using the Wisconsin card-sorting test and continuous performance test. RESULTS: euBD performed worse on attentional function than controls (p = 0.001). Compared to controls, euBD had higher E/I ratios in the PCC (p = 0.023), mainly driven by a higher Glx level in the PCC of euBD (p = 0.002). Only in the BD group, a marginally significant negative association between the mPFC E/I ratio (Glx/GABA) and executive function was observed (p = 0.068). CONCLUSIONS: Disturbed E/I balance, particularly elevated Glx/GABA ratio in PCC is observed in euBD. The E/I balance in hubs of DMN may serve as potential biomarkers for euBD, which may also contribute to their poorer executive function.

Excitatory and inhibitory synapses show a tight subcellular correlation that weakens over development.

Neurons receive correlated levels of excitation and inhibition, a feature that is important for proper brain function. However, how this relationship between excitatory and inhibitory inputs is established during the dynamic period of circuit wiring remains unexplored. Using multiple techniques, including in utero electroporation, electron microscopy, and electrophysiology, we reveal a tight correlation in the distribution of excitatory and inhibitory synapses along the dendrites of developing CA1 hippocampal neurons. This correlation was present within short dendritic stretches (<20 µm) and, surprisingly, was most pronounced during early development, sharply declining with maturity. The tight matching between excitation and inhibition was unexpected, as inhibitory synapses lacked an active zone when formed and exhibited compromised evoked release. We propose that inhibitory synapses form as a stabilizing scaffold to counterbalance growing excitation levels. This relationship diminishes over time, suggesting a critical role for a subcellular balance in early neuronal function and circuit formation.

Exploration of interictal to ictal transition in epileptic seizures using a neural mass model.

An epileptic seizure can usually be divided into three stages: interictal, preictal, and ictal. However, the seizure underlying the transition from interictal to ictal activities in the brain involves complex interactions between inhibition and excitation in groups of neurons. To explore this mechanism at the level of a single population, this paper employed a neural mass model, named the complete physiology-based model (cPBM), to reconstruct electroencephalographic (EEG) signals and to infer the changes in excitatory/inhibitory connections related to excitation-inhibition (E-I) balance based on an open dataset recorded for ten epileptic patients. Since epileptic signals display spectral characteristics, spectral dynamic causal modelling (DCM) was applied to quantify these frequency characteristics by maximizing the free energy in the framework of power spectral density (PSD) and estimating the cPBM parameters. In addition, to address the local maximum problem that DCM may suffer from, a hybrid deterministic DCM (H-DCM) approach was proposed, with a deterministic annealing-based scheme applied in two directions. The H-DCM approach adjusts the temperature introduced in the objective function by gradually decreasing the temperature to obtain relatively good initialization and then gradually increasing the temperature to search for a better estimation after each maximization. The results showed that (i) reconstructed EEG signals belonging to the three stages together with their PSDs can be reproduced from the estimated parameters of the cPBM; (ii) compared to DCM, traditional D-DCM and anti D-DCM, the proposed H-DCM shows higher free energies and lower root mean square error (RMSE), and it provides the best performance for all stages (e.g., the RMSEs between the reconstructed PSD computed from the reconstructed EEG signal and the sample PSD obtained from the real EEG signal are 0.33 ± 0.08, 0.67 ± 0.37 and 0.78 ± 0.57 in the interictal, preictal and ictal stages, respectively); and (iii) the transition from interictal to ictal activity can be explained by an increase in the connections between pyramidal cells and excitatory interneurons and between pyramidal cells and fast inhibitory interneurons, as well as a decrease in the self-loop connection of the fast inhibitory interneurons in the cPBM. Moreover, the E-I balance, defined as the ratio between the excitatory connection from pyramidal cells to fast inhibitory interneurons and the inhibitory connection with the self-loop of fast inhibitory interneurons, is also significantly increased during the epileptic seizure transition. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09976-6.

Neurometabolite differences in Autism as assessed with Magnetic Resonance Spectroscopy: A systematic review and meta-analysis.

1H-Magnetic Resonance Spectroscopy (MRS) is a non-invasive technique that can be used to quantify the concentrations of metabolites in the brain in vivo. MRS findings in the context of autism are inconsistent and conflicting. We performed a systematic review and meta-analysis of MRS studies measuring glutamate and gamma-aminobutyric acid (GABA), as well as brain metabolites involved in energy metabolism (glutamine, creatine), neural and glial integrity (e.g. n-acetyl aspartate (NAA), choline, myo-inositol) and oxidative stress (glutathione) in autism cohorts. Data were extracted and grouped by metabolite, brain region and several other factors before calculation of standardised effect sizes. Overall, we find significantly lower concentrations of GABA and NAA in autism, indicative of disruptions to the balance between excitation/inhibition within brain circuits, as well as neural integrity. Further analysis found these alterations are most pronounced in autistic children and in limbic brain regions relevant to autism phenotypes. Additionally, we show how study outcome varies due to demographic and methodological factors , emphasising the importance of conforming with standardised consensus study designs and transparent reporting.

Scn1a haploinsufficiency in the prefrontal cortex engages to cognitive impairment and depressive phenotype.

Altered development and function of the prefrontal cortex (PFC) during adolescence is implicated in the origin of mental disorders. Deficits in the GABAergic system prominently contribute to these alterations. Nav1.1 is a voltage-gated Na+ channel critical for normal GABAergic activity. Here, we studied the role of Nav1.1 in PFC function and its potential relationship with the aetiology of mental disorders. Dysfunction of Nav1.1 activity in the medial PFC (mPFC) of adolescent mice enhanced the local excitation/inhibition ratio, resulting in epileptic activity, cognitive deficits and depressive-like behaviour in adulthood, along with a gene expression profile linked to major depressive disorder (MDD). Additionally, it reduced extracellular serotonin concentration in the dorsal raphe nucleus and brain-derived neurotrophic factor expression in the hippocampus, two MDD-related brain areas beyond the PFC. We also observed alterations in oscillatory activity and impaired hippocampal-mPFC coherence during sleep. Finally, we found reduced expression levels of SCN1A, the gene encoding Nav1.1, in post-mortem PFC samples from human MDD subjects. Collectively, our results provide a novel mechanistic framework linking adolescence-specific alterations in Nav1.1 function in the PFC to the pathogenesis of epilepsy and comorbidities such as cognitive impairment and depressive disorders.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.

GABAergic interneuron diversity and organization are crucial for the generation of human-specific functional neural networks in cerebral organoids.

This mini review investigates the importance of GABAergic interneurons for the network function of human-induced pluripotent stem cells (hiPSC)-derived brain organoids. The presented evidence suggests that the abundance, diversity and three-dimensional cortical organization of GABAergic interneurons are the primary elements responsible for the creation of synchronous neuronal firing patterns. Without intricate inhibition, coupled oscillatory patterns cannot reach a sufficient complexity to transfer spatiotemporal information constituting physiological network function. Furthermore, human-specific brain network function seems to be mediated by a more complex and interconnected inhibitory structure that remains developmentally flexible for a longer period when compared to rodents. This suggests that several characteristics of human brain networks cannot be captured by rodent models, emphasizing the need for model systems like organoids that adequately mimic physiological human brain function in vitro.

Assessing cortical excitability with electroencephalography: A pilot study with EEG-iTBS.

BACKGROUND: Cortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals and termed 'intrinsic excitability' measures. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of TMS cortical excitability and E/I of the stimulated hemisphere. OBJECTIVE: Investigating to what extent E/I estimates scale with TMS excitability and how they relate to each other. METHODS: M1 excitability (TMS) and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. RESULTS: Enhancement of TMS M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or strong consistency with each other. CONCLUSIONS: EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.

From synapses to circuits: What mouse models have taught us about how autism spectrum disorder impacts hippocampal function.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that impacts a variety of cognitive and behavioral domains. While a genetic component of ASD has been well-established, none of the numerous syndromic genes identified in humans accounts for more than 1% of the clinical patients. Due to this large number of target genes, numerous mouse models of the disorder have been generated. However, the focus on distinct brain circuits, behavioral phenotypes and diverse experimental approaches has made it difficult to synthesize the overwhelming number of model animal studies into concrete throughlines that connect the data across levels of investigation. Here we chose to focus on one circuit, the hippocampus, and one hypothesis, a shift in excitatory/inhibitory balance, to examine, from the level of the tripartite synapse up to the level of in vivo circuit activity, the key commonalities across disparate models that can illustrate a path towards a better mechanistic understanding of ASD's impact on hippocampal circuit function.

Medication-invariant resting aperiodic and periodic neural activity in Parkinson's disease.

Parkinson's disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open (EO) and eyes-closed (EC) resting EEG of PD participants (N = 26) on and off medication, and age-matched healthy controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in EO recordings and no reliable differences in beta power were observed. Differences between PD and CTL in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.

Microglia induce auditory dysfunction after status epilepticus in mice.

Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus. We further demonstrated that microglia reduced inhibitory synapses on MGB relay neurons over an 8-week period after status epilepticus, resulting in auditory pathway hyperactivity. In addition, we found that local removal of microglia from the MGB attenuated the increase in c-Fos+ relay neurons and improved auditory discrimination. These findings reveal that thalamic microglia are involved in auditory dysfunction in epilepsy.

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.

Glial regulation of critical period plasticity.

Animal behavior, from simple to complex, is dependent on the faithful wiring of neurons into functional neural circuits. Neural circuits undergo dramatic experience-dependent remodeling during brief developmental windows called critical periods. Environmental experience during critical periods of plasticity produces sustained changes to circuit function and behavior. Precocious critical period closure is linked to autism spectrum disorders, whereas extended synaptic remodeling is thought to underlie circuit dysfunction in schizophrenia. Thus, resolving the mechanisms that instruct critical period timing is important to our understanding of neurodevelopmental disorders. Control of critical period timing is modulated by neuron-intrinsic cues, yet recent data suggest that some determinants are derived from neighboring glial cells (astrocytes, microglia, and oligodendrocytes). As glia make up 50% of the human brain, understanding how these diverse cells communicate with neurons and with each other to sculpt neural plasticity, especially during specialized critical periods, is essential to our fundamental understanding of circuit development and maintenance.

Multilevel and multifaceted brain response features in spiking, ERP and ERD: experimental observation and simultaneous generation in a neuronal network model with excitation-inhibition balance.

Brain as a dynamic system responds to stimulations with specific patterns affected by its inherent ongoing dynamics. The patterns are manifested across different levels of organization-from spiking activity of neurons to collective oscillations in local field potential (LFP) and electroencephalogram (EEG). The multilevel and multifaceted response activities show patterns seemingly distinct and non-comparable from each other, but they should be coherently related because they are generated from the same underlying neural dynamic system. A coherent understanding of the interrelationships between different levels/aspects of activity features is important for understanding the complex brain functions. Here, based on analysis of data from human EEG, monkey LFP and neuronal spiking, we demonstrated that the brain response activities from different levels of neural system are highly coherent: the external stimulus simultaneously generated event-related potentials, event-related desynchronization, and variation in neuronal spiking activities that precisely match with each other in the temporal unfolding. Based on a biologically plausible but generic network of conductance-based integrate-and-fire excitatory and inhibitory neurons with dense connections, we showed that the multiple key features can be simultaneously produced at critical dynamical regimes supported by excitation-inhibition (E-I) balance. The elucidation of the inherent coherency of various neural response activities and demonstration of a simple dynamical neural circuit system having the ability to simultaneously produce multiple features suggest the plausibility of understanding high-level brain function and cognition from elementary and generic neuronal dynamics. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09889-w.

The autism spectrum disorder risk gene NEXMIF over-synchronizes hippocampal CA1 network and alters neuronal coding.

Mutations in autism spectrum disorder (ASD) risk genes disrupt neural network dynamics that ultimately lead to abnormal behavior. To understand how ASD-risk genes influence neural circuit computation during behavior, we analyzed the hippocampal network by performing large-scale cellular calcium imaging from hundreds of individual CA1 neurons simultaneously in transgenic mice with total knockout of the X-linked ASD-risk gene NEXMIF (neurite extension and migration factor). As NEXMIF knockout in mice led to profound learning and memory deficits, we examined the CA1 network during voluntary locomotion, a fundamental component of spatial memory. We found that NEXMIF knockout does not alter the overall excitability of individual neurons but exaggerates movement-related neuronal responses. To quantify network functional connectivity changes, we applied closeness centrality analysis from graph theory to our large-scale calcium imaging datasets, in addition to using the conventional pairwise correlation analysis. Closeness centrality analysis considers both the number of connections and the connection strength between neurons within a network. We found that in wild-type mice the CA1 network desynchronizes during locomotion, consistent with increased network information coding during active behavior. Upon NEXMIF knockout, CA1 network is over-synchronized regardless of behavioral state and fails to desynchronize during locomotion, highlighting how perturbations in ASD-implicated genes create abnormal network synchronization that could contribute to ASD-related behaviors.