Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes.

Neurodevelopmental disorders (NDDs) include a broad spectrum of pathological conditions that affect >4% of children worldwide, share common features and present a variegated genetic origin. They include clinically defined diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), motor disorders such as Tics and Tourette's syndromes, but also much more heterogeneous conditions like intellectual disability (ID) and epilepsy. Schizophrenia (SCZ) has also recently been proposed to belong to NDDs. Relatively common causes of NDDs are copy number variations (CNVs), characterised by the gain or the loss of a portion of a chromosome. In this review, we focus on deletions and duplications at the 16p11.2 chromosomal region, associated with NDDs, ID, ASD but also epilepsy and SCZ. Some of the core phenotypes presented by human carriers could be recapitulated in animal and cellular models, which also highlighted prominent neurophysiological and signalling alterations underpinning 16p11.2 CNVs-associated phenotypes. In this review, we also provide an overview of the genes within the 16p11.2 locus, including those with partially known or unknown function as well as non-coding RNAs. A particularly interesting interplay was observed between MVP and MAPK3 in modulating some of the pathological phenotypes associated with the 16p11.2 deletion. Elucidating their role in intracellular signalling and their functional links will be a key step to devise novel therapeutic strategies for 16p11.2 CNVs-related syndromes.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

Effects of N-Methyl-d-Aspartate Receptor Antagonists on Gamma-Band Activity During Auditory Stimulation Compared With Electro/Magneto-encephalographic Data in Schizophrenia and Early-Stage Psychosis: A Systematic Review and Perspective.

BACKGROUND AND HYPOTHESIS: N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity. STUDY DESIGN: This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power. STUDY RESULTS: Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients. CONCLUSIONS: Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.

Defined co-cultures of glutamatergic and GABAergic neurons with a mutation in DISC1 reveal aberrant phenotypes in GABAergic neurons.

BACKGROUND: Mutations in the gene DISC1 are associated with increased risk for schizophrenia, bipolar disorder and major depression. The study of mutated DISC1 represents a well-known and comprehensively characterized approach to understand neuropsychiatric disease mechanisms. However, previous studies have mainly used animal models or rather heterogeneous populations of iPSC-derived neurons, generated by undirected differentiation, to study the effects of DISC1 disruption. Since major hypotheses to explain neurodevelopmental, psychiatric disorders rely on altered neuronal connectivity observed in patients, an ideal iPSC-based model requires accurate representation of the structure and complexity of neuronal circuitries. In this study, we made use of an isogenic cell line with a mutation in DISC1 to study neuronal synaptic phenotypes in a culture system comprising a defined ratio of NGN2 and ASCL1/DLX2 (AD2)-transduced neurons, enriched for glutamatergic and GABAergic neurons, respectively, to mimic properties of the cortical microcircuitry. RESULTS: In heterozygous DISC1 mutant neurons, we replicated the expected phenotypes including altered neural progenitor proliferation as well as neurite outgrowth, deregulated DISC1-associated signaling pathways, and reduced synaptic densities in cultures composed of glutamatergic neurons. Cultures comprising a defined ratio of NGN2 and AD2 neurons then revealed considerably increased GABAergic synapse densities, which have not been observed in any iPSC-derived model so far. Increased inhibitory synapse densities could be associated with an increased efficiency of GABAergic differentiation, which we observed in AD2-transduced cultures of mutant neurons. Additionally, we found increased neuronal activity in GABAergic neurons through calcium imaging while the activity pattern of glutamatergic neurons remained unchanged. CONCLUSIONS: In conclusion, our results demonstrate phenotypic differences in a co-culture comprising a defined ratio of DISC1 mutant NGN2 and AD2 neurons, as compared to culture models comprising only one neuronal cell type. Altered synapse numbers and neuronal activity imply that DISC1 impacts the excitatory/inhibitory balance in NGN2/AD2 co-cultures, mainly through increased GABAergic input.

Neuronal imbalance of excitation and inhibition in schizophrenia: a scoping review of gamma-band ASSR findings.

Recent empirical findings suggest that altered neural synchronization, which is hypothesized to be associated with an imbalance of excitatory (E) and inhibitory (I) neuronal activities, may underlie a core pathophysiological mechanism in patients with schizophrenia. The auditory steady-state response (ASSR) examined by electroencephalography (EEG) and magnetoencephalography (MEG) has been proposed as a potential biomarker for evaluating altered neural synchronization in schizophrenia. For this review, we performed a comprehensive literature search for papers published between 1999 and 2021 examining ASSRs in patients with schizophrenia. Almost all EEG-ASSR studies reported gamma-band ASSR reductions, especially to 40-Hz stimuli both in power and/or phase synchronization in chronic and first-episode schizophrenia. In addition, similar to EEG-ASSR findings, MEG-ASSR deficits to 80-Hz stimuli (high gamma) have been reported in patients with schizophrenia. Moreover, the 40-Hz ASSR is likely to be a predictor of the onset of schizophrenia. Notably, increased spontaneous (or ongoing) broadband (30-100 Hz) gamma power has been reported during ASSR tasks, which resembles the increased spontaneous gamma activity reported in animal models of E/I imbalance. Further research on ASSRs and evoked and spontaneous gamma oscillations is expected to elucidate the pathophysiology of schizophrenia with translational implications.

Dysfunction of the Hippocampal-Lateral Septal Circuit Impairs Risk Assessment in Epileptic Mice.

Temporal lobe epilepsy, a chronic disease of the brain characterized by degeneration of the hippocampus, has impaired risk assessment. Risk assessment is vital for survival in complex environments with potential threats. However, the underlying mechanisms remain largely unknown. The intricate balance of gene regulation and expression across different brain regions is related to the structure and function of specific neuron subtypes. In particular, excitation/inhibition imbalance caused by hyperexcitability of glutamatergic neurons and/or dysfunction of GABAergic neurons, have been implicated in epilepsy. First, we estimated the risk assessment (RA) by evaluating the behavior of mice in the center of the elevated plus maze, and found that the kainic acid-induced temporal lobe epilepsy mice were specifically impaired their RA. This experiment evaluated approach-RA, with a forthcoming approach to the open arm, and avoid-RA, with forthcoming avoidance of the open arm. Next, results from free-moving electrophysiological recordings showed that in the hippocampus, ∼7% of putative glutamatergic neurons and ∼15% of putative GABAergic neurons were preferentially responsive to either approach-risk assessment or avoid-risk assessment, respectively. In addition, ∼12% and ∼8% of dorsal lateral septum GABAergic neurons were preferentially responsive to approach-risk assessment and avoid-risk assessment, respectively. Notably, during the impaired approach-risk assessment, the favorably activated dorsal dentate gyrus and CA3 glutamatergic neurons increased (∼9%) and dorsal dentate gyrus and CA3 GABAergic neurons decreased (∼7%) in the temporal lobe epilepsy mice. Then, we used RNA sequencing and immunohistochemical staining to investigate which subtype of GABAergic neuron loss may contribute to excitation/inhibition imbalance. The results show that temporal lobe epilepsy mice exhibit significant neuronal loss and reorganization of neural networks. In particular, the dorsal dentate gyrus and CA3 somatostatin-positive neurons and dorsal lateral septum cholecystokinin-positive neurons are selectively vulnerable to damage after temporal lobe epilepsy. Optogenetic activation of the hippocampal glutamatergic neurons or chemogenetic inhibition of the hippocampal somatostatin neurons directly disrupts RA, suggesting that an excitation/inhibition imbalance in the dHPC dorsal lateral septum circuit results in the impairment of RA behavior. Taken together, this study provides insight into epilepsy and its comorbidity at different levels, including molecular, cell, neural circuit, and behavior, which are expected to decrease injury and premature mortality in patients with epilepsy.

Autism-Like Behavioral Phenotypes in Mice Treated with Systemic N-Methyl-D-Aspartate.

Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

General Anesthesia During Neurodevelopment Reduces Autistic Behavior in Adult BTBR Mice, a Murine Model of Autism.

Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.

A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms.

Schizophrenia is a chronic disorder characterized by specific positive and negative primary symptoms, social behavior disturbances and cognitive deficits (e.g., impairment in working memory and cognitive flexibility). Mounting evidence suggests that altered excitability and inhibition at the molecular, cellular, circuit and network level might be the basis for the pathophysiology of neurodevelopmental and neuropsychiatric disorders such as schizophrenia. In the past decades, human and animal studies have identified that glutamate and gamma-aminobutyric acid (GABA) neurotransmissions are critically involved in several cognitive progresses, including learning and memory. The purpose of this review is, by analyzing emerging findings relating to the balance of excitatory and inhibitory, ranging from animal models of schizophrenia to clinical studies in patients with early onset, first-episode or chronic schizophrenia, to discuss how the excitatory-inhibitory imbalance may relate to the pathophysiology of disease phenotypes such as cognitive deficits and negative symptoms, and highlight directions for appropriate therapeutic strategies.

Epileptic Mechanisms Shared by Alzheimer's Disease: Viewed via the Unique Lens of Genetic Epilepsy.

Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer's disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABAA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.

Depression-like behavior associated with E/I imbalance of mPFC and amygdala without TRPC channels in mice of knockout IL-10 from microglia.

Depression has a growing impact on public health. Accumulating evidence supports an association between depression and increased immune system activity. IL-10 is a key cytokine that inhibits excessive inflammatory responses and is related to the anti-inflammatory and protective functions of the central nervous system (CNS). Cx3cr1CreERIL-10-/- mice were used in our study. We aimed to identify the role of IL-10 in microglia in depression and anxiety-like behavior. We performed a series of behavioral tests on the mice; the Cx3cr1CreERIL-10-/- male mice showed depression- and anxiety-like behavior compared with the littermates. The expression of transient receptor potential canonical 5 (TRPC5) decreased in both the medial prefrontal cortex (mPFC) and amygdala regions. The cytokines IL-1ß and IL-6 increased, and IL-10 was decreased by western blotting. The knockout mice showed different trends in the effects of synaptic proteins. In the mPFC, IL-10 knockout induced a decrease in NR2B and synaptophysin; in the amygdala region, there was a significant increase in NR2B and PSD95. IL-10 knockout from microglia induced a decrease in GAD67 and parvalbumin (Pv) in the mPFC, but not in the amygdala. Our results showed enhanced depression and anxiety-like behavior in the Cx3cr1CreER IL-10-/- mice, which could be related to an imbalance in local excitatory and inhibitory transmission, as well as neuroinflammation in the mPFC and amygdala. This imbalance was associated with increased local inflammation. Although many studies have demonstrated the role of TRPC channels in emotional responses, our study showed that TRPC was not involved in this process in Cx3cr1CreERIL-10-/- mice.

Do NMDA-R antagonists re-create patterns of spontaneous gamma-band activity in schizophrenia? A systematic review and perspective.

NMDA-R hypofunctioninig is a core pathophysiological mechanism in schizophrenia. However, it is unclear whether the physiological changes observed following NMDA-R antagonist administration are consistent with gamma-band alterations in schizophrenia. This systematic review examined the effects of NMDA-R antagonists on the amplitude of spontaneous gamma-band activity and functional connectivity obtained from preclinical (n = 24) and human (n = 9) studies and compared these data to resting-state EEG/MEG-measurements in schizophrenia patients (n = 27). Overall, the majority of preclinical and human studies observed increased gamma-band power following acute administration of NMDA-R antagonists. However, the direction of gamma-band power alterations in schizophrenia were inconsistent, which involved upregulation (n = 10), decreases (n = 7), and no changes (n = 8) in spectral power. Five out of 6 preclinical studies observed increased connectivity, while in healthy controls receiving Ketamine and in schizophrenia patients the direction of connectivity results was also inconsistent. Accordingly, the effects of NMDA-R hypofunctioning on gamma-band oscillations are different than pathophysiological signatures observed in schizophrenia. The implications of these findings for current E/I balance models of schizophrenia are discussed.

Homogeneous Intrinsic Neuronal Excitability Induces Overfitting to Sensory Noise: A Robot Model of Neurodevelopmental Disorder.

Neurodevelopmental disorders, including autism spectrum disorder, have been intensively investigated at the neural, cognitive, and behavioral levels, but the accumulated knowledge remains fragmented. In particular, developmental learning aspects of symptoms and interactions with the physical environment remain largely unexplored in computational modeling studies, although a leading computational theory has posited associations between psychiatric symptoms and an unusual estimation of information uncertainty (precision), which is an essential aspect of the real world and is estimated through learning processes. Here, we propose a mechanistic explanation that unifies the disparate observations via a hierarchical predictive coding and developmental learning framework, which is demonstrated in experiments using a neural network-controlled robot. The results show that, through the developmental learning process, homogeneous intrinsic neuronal excitability at the neural level induced via self-organization changes at the information processing level, such as hyper sensory precision and overfitting to sensory noise. These changes led to multifaceted alterations at the behavioral level, such as inflexibility, reduced generalization, and motor clumsiness. In addition, these behavioral alterations were accompanied by fluctuating neural activity and excessive development of synaptic connections. These findings might bridge various levels of understandings in autism spectrum and other neurodevelopmental disorders and provide insights into the disease processes underlying observed behaviors and brain activities in individual patients. This study shows the potential of neurorobotics frameworks for modeling how psychiatric disorders arise from dynamic interactions among the brain, body, and uncertain environments.

Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation.

Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features and investigate their neurodevelopmental alterations. Mut hESCs overproduce ventral telencephalic neuron progenitors (ventral NPCs) and underproduce dorsal NPCs, causing the imbalance of excitatory/inhibitory neurons. These alterations can be mainly attributed to the aberrantly activated Hedgehog signaling pathway. Moreover, the corresponding Nr2f1 point-mutant mice display a similar excitatory/inhibitory neuron imbalance and abnormal behaviors. Antagonizing the increased inhibitory synaptic transmission partially alleviates their behavioral deficits. Together, our results suggest that the NR2F1-dependent imbalance of excitatory/inhibitory neuron differentiation caused by the activated Hedgehog pathway is one precursor of neurodevelopmental disorders and may enlighten the therapeutic approaches.

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia.

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients.

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene. Deficient K+-Cl-co-transporter 2 (KCC2) expression is suggested to play a key role in the neurodevelopmental delay in RTT patients' neuronal networks. KCC2 is a major player in neuronal maturation by supporting the GABAergic switch, through the regulation of neuronal chlorine homeostasis. Previous studies suggest that MeCP2 mutations lead to changed KCC2 expression levels, thereby causing a disturbance in excitation/inhibition (E/I) balance. To investigate this, we performed protein and RNA expression analysis on post mortem brain tissue from RTT patients and healthy controls. We showed that KCC2 expression, in particular the KCC2a isoform, is relatively decreased in RTT patients. The expression of Na+-K+-Cl- co-transporter 1 (NKCC1), responsible for the inward transport of chlorine, is not affected, leading to a reduced KCC2/NKCC1 ratio in RTT brains. Our report confirms KCC2 expression alterations in RTT patients in human brain tissue, which is in line with other studies, suggesting affected E/I balance could underlie neurodevelopmental defects in RTT patients.

Autophagy links MTOR and GABA signaling in the brain.

The disruption of MTOR-regulated macroautophagy/autophagy was previously shown to cause autistic-like abnormalities; however, the underlying molecular defects remained largely unresolved. In a recent study, we demonstrated that autophagy deficiency induced by conditional Atg7 deletion in either forebrain GABAergic inhibitory or excitatory neurons leads to a similar set of autistic-like behavioral abnormalities even when induced following the peak period of synaptic pruning during postnatal neurodevelopment. Our proteomic analysis and molecular dissection further revealed a mechanism in which the GABAA receptor trafficking function of GABARAP (gamma-aminobutyric acid receptor associated protein) family proteins was compromised as they became sequestered by SQSTM1/p62-positive aggregates formed due to autophagy deficiency. Our discovery of autophagy as a link between MTOR and GABA signaling may have implications not limited to neurodevelopmental and neuropsychiatric disorders, but could potentially be involved in other human pathologies such as cancer and diabetes in which both pathways are implicated.

NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model.

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.