Targeting epigenetic enzymes for autism treatment.

Emerging preclinical autism research has shown the therapeutic promise of pharmacological inhibitors for epigenetic enzymes, such as histone deacetylases (HDAC), euchromatic histone methyltransferases (EHMT), and lysine-specific histone demethylase 1A (LSD1). These interventions restore gene expression, synaptic function, and behavioral performance in autism models, highlighting a new strategy for autism treatment.

Cannabidiol is a behavioral modulator in BTBR mouse model of idiopathic autism.

Introduction: The prevalence of Autism Spectrum Disorder (ASD) has drastically risen over the last two decades and is currently estimated to affect 1 in 36 children in the U.S., according to the center for disease control (CDC). This heterogenous neurodevelopmental disorder is characterized by impaired social interactions, communication deficits, and repetitive behaviors plus restricted interest. Autistic individuals also commonly present with a myriad of comorbidities, such as attention deficit hyperactivity disorder, anxiety, and seizures. To date, a pharmacological intervention for the treatment of core autistic symptoms has not been identified. Cannabidiol (CBD), the major nonpsychoactive constituent of Cannabis sativa, is suggested to have multiple therapeutic applications, but its effect(s) on idiopathic autism is unknown. We hypothesized that CBD will effectively attenuate the autism-like behaviors and autism-associated comorbid behaviors in BTBR T+Itpr3tf/J (BTBR) mice, an established mouse model of idiopathic ASD. Methods: Male BTBR mice were injected intraperitoneally with either vehicle, 20 mg/kg CBD or 50 mg/kg CBD daily for two weeks beginning at postnatal day 21 ± 3. On the final treatment day, a battery of behavioral assays were used to evaluate the effects of CBD on the BTBR mice, as compared to age-matched, vehicle-treated C57BL/6 J mice. Results: High dose (50 mg/kg) CBD treatment attenuated the elevated repetitive self-grooming behavior and hyperlocomotion in BTBR mice. The social deficits exhibited by the control BTBR mice were rescued by the 20 mg/kg CBD treatment. Discussion: Our data indicate that different doses for CBD are needed for treating specific ASD-like behaviors. Together, our results suggest that CBD may be an effective drug to ameliorate repetitive/restricted behaviors, social deficits, and autism-associated hyperactivity.

Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model.

BACKGROUND: Microdeletion of the human chromosomal region 16p11.2 (16p11.2 + / - ) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2 + / -  syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2 + / -  are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2 + / - , as well as the underlying molecular mechanisms. RESULTS: Mice with the 16p11.2 + / -  showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene. CONCLUSIONS: Our study reveals that 16p11.2 + / -  leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2 + / -  mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome. Video Abstract.

The reciprocal associations between social deficits, social engagement, and inflammation: Longitudinal evidence comparing venous blood samples and dried blood spots and mapping the modifying role of phenotypic and genotypic depression.

BACKGROUND: Social psychoneuroimmunology suggests an interplay between social deficits (loneliness and isolation) and chronic inflammation, but the direction of these relationships remains unclear. We estimated the reciprocal associations of social deficits and social engagement with levels of C-reactive protein (CRP), compared the consistency of the findings depending on the biological sampling method used, and examined the modifying role of phenotypic and genotypic depression. METHODS: We used longitudinal nationally representative data from the US (Health and Retirement Study, 3 waves, 2006-16) and England (English Longitudinal Study of Ageing, 4 waves, 2004-18). Loneliness, social isolation, and social engagement were self-reported. CRP was measured using dried blood spots (US) and venous blood samples (England). Cross-lagged panel models were fitted and tested interactions with phenotypic depression (above-threshold depressive symptom scores) and genotypic depression (polygenic score for major depressive disorder). RESULTS: We included 15,066 participants (mean age = 66.1 years, SD = 9.8) in the US and 10,290 (66.9 years, SD = 10.5) in England. We found reciprocal associations between loneliness and CRP using dried blood spots and venous blood samples. Higher CRP predicted higher subsequent loneliness and higher loneliness predicted elevated CRP. Both phenotypic and genotypic depression modified this reciprocal association. There were also reciprocal associations for social engagement in venous blood samples: higher CRP predicted lower social engagement and greater social engagement predicted lower subsequent CRP. Associations between social isolation and CRP were inconsistent and unidirectional. CONCLUSIONS: Loneliness may increase chronic inflammation, whereas social engagement may reduce inflammation. As these relationships were reciprocal, there may be a loop between inflammation, loneliness, and social engagement. This loop was stronger in those with depression or at high genetic risk for major depressive disorder. This relationship for loneliness was present in both blood sampling methods despite contrasting methods of CRP measurement, indicating that the finding is not attributable to measurement bias in biomarkers.

Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization.

BACKGROUND: 15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited. METHODS: Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype. RESULTS: Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination. CONCLUSIONS: Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.

Social withdrawal and anxiety-like behavior have an impact on zebrafish adult neurogenesis.

Introduction: Accumulating evidence highlights the key role of adult neurogenesis events in environmental challenges, cognitive functions and mood regulation. Abnormal hippocampal neurogenesis has been implicated in anxiety-like behaviors and social impairments, but the possible mechanisms remain elusive. Methods: The present study questioned the contribution of altered excitation/inhibition as well as excessive neuroinflammation in regulating the neurogenic processes within the Social Decision-Making (SDM) network, using an adult zebrafish model displaying NMDA receptor hypofunction after sub-chronic MK-801 administration. For this, the alterations in cell proliferation and newborn cell densities were evaluated using quantitative 5-Bromo-2'-Deoxyuridine (BrdU) methodology. Results: In short-term survival experiments. MK-801-treated zebrafish displayed decreased cell proliferation pattern within distinct neurogenic zones of telencephalic and preoptic SDM nodes, in parallel to the social withdrawal and anxiety-like comorbidity. BrdU+ cells co-expressed the pro-inflammatory marker IL-1ß solely in MK-801-treated zebrafish, indicating a role of inflammation. Following the cessation of drug treatment, significant increases in the BrdU+ cell densities were accompanied by the normalization of the social and anxiety-like phenotype. Importantly, most labeled cells in neurogenic zones showed a radial glial phenotype while a population of newborn cells expressed the early neuronal marker TOAD or mGLuR5, the latter suggesting the possible involvement of metabotropic glutamate receptor 5 in neurogenic events. Discussion: Overall, our results indicate the role of radial glial cell proliferation in the overlapping pathologies of anxiety and social disorders, observed in many neuropsychiatric disorders and possibly represent potential novel targets for amelioration of these symptoms.

Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior.

Introduction: Deficits in social communication are in the core of clinical symptoms characterizing many neuropsychiatric disorders such as schizophrenia and autism spectrum disorder. The occurrence of anxiety-related behavior, a common co-morbid condition in individuals with impairments in social domain, suggests the presence of overlapping neurobiological mechanisms between these two pathologies. Dysregulated excitation/inhibition balance and excessive neuroinflammation, in specific neural circuits, are proposed as common etiological mechanisms implicated in both pathologies. Methods and Results: In the present study we evaluated changes in glutamatergic/GABAergic neurotransmission as well as the presence of neuroinflammation within the regions of the Social Decision-Making Network (SDMN) using a zebrafish model of NMDA receptor hypofunction, following sub-chronic MK-801 administration. MK-801-treated zebrafish are characterized by impaired social communication together with increased anxiety levels. At the molecular level, the behavioral phenotype was accompanied by increased mGluR5 and GAD67 but decreased PSD-95 protein expression levels in telencephalon and midbrain. In parallel, MK-801-treated zebrafish exhibited altered endocannabinoid signaling as indicated by the upregulation of cannabinoid receptor 1 (CB1R) in the telencephalon. Interestingly, glutamatergic dysfunction was positively correlated with social withdrawal behavior whereas defective GABAergic and endocannabinoid activity were positively associated with anxiety-like behavior. Moreover, neuronal and astrocytic IL-1ß expression was increased in regions of the SDMN, supporting the role of neuroinflammatory responses in the manifestation of MK-801 behavioral phenotype. Colocalization of interleukin-1ß (IL-1ß) with ß2-adrenergic receptors (ß2-ARs) underlies the possible influence of noradrenergic neurotransmission to increased IL-1ß expression in comorbidity between social deficits and elevated anxiety comorbidity. Discussion: Overall, our results indicate the contribution of altered excitatory and inhibitory synaptic transmission as well as excessive neuroinflammatory responses in the manifestation of social deficits and anxiety-like behavior of MK-801-treated fish, identifying possible novel targets for amelioration of these symptoms.

Understanding the Relationship between Distress Behaviour and Health Status of People with Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is associated with complex distress and challenging behaviours that have a negative impact on the everyday life of those with ASD, as well as their parents and carers. These challenging behaviours include negative emotional behaviours, motor behaviours, and changes in routines. Even though challenging behaviours occur in most subjects with ASD, the cause of these largely remains unknown. It has been implicated that these challenging behaviours are associated with a change in the health of those with ASD. More research needs to be conducted that can establish a direct association. Towards this goal, the present study aimed to explore whether health status had an impact on the distressing behaviour in the subjects diagnosed with ASD. We analysed the response from the parents/carers in a Macedonian population of those with ASD, to determine which challenging behaviours were most likely to be observed during a change in health. Based on a scoring system, the manifestation of challenging behaviour was evaluated and compared with the changes in health. Changes in appetite or dietary preferences, irritability and low mood, and loss of previously acquired skills had the greatest association with a change in health. These findings provide early insight into types of challenging behaviours that are directly associated with a change in health. Our results demonstrate a relationship between health status and challenging behaviour in the subject with autism, suggesting that caregivers may need to consider this when choosing strategies for managing challenging behaviour.

Involvement of oxytocin receptor deficiency in psychiatric disorders and behavioral abnormalities.

Oxytocin and its target receptor (oxytocin receptor, OXTR) exert important roles in the regulation of complex social behaviors and cognition. The oxytocin/OXTR system in the brain could activate and transduce several intracellular signaling pathways to affect neuronal functions or responses and then mediate physiological activities. The persistence and outcome of the oxytocin activity in the brain are closely linked to the regulation, state, and expression of OXTR. Increasing evidence has shown that genetic variations, epigenetic modification states, and the expression of OXTR have been implicated in psychiatric disorders characterized by social deficits, especially in autism. Among these variations and modifications, OXTR gene methylation and polymorphism have been found in many patients with psychiatric disorders and have been considered to be associated with those psychiatric disorders, behavioral abnormalities, and individual differences in response to social stimuli or others. Given the significance of these new findings, in this review, we focus on the progress of OXTR's functions, intrinsic mechanisms, and its correlations with psychiatric disorders or deficits in behaviors. We hope that this review can provide a deep insight into the study of OXTR-involved psychiatric disorders.

Transient hearing abnormalities precede social deficits in a mouse model of autism.

Hearing abnormalities are important symptoms of autism spectrum disorders (ASDs), a neurological and developmental disorder. However, the characteristics of hearing abnormalities associated with ASD during development have not been fully investigated. We found that in Shank3B knockout mice (a high-confidence mouse model of ASD), transient hearing abnormalities can be found in auditory brainstem response, auditory cortical activity, as well as acoustic startle response. More importantly, all hearing abnormalities at 4 weeks were most prominent and preceded the onset of social deficits at 6 weeks. These hearing abnormalities gradually recovered with age. In addition, analysis of ABR data at 4 weeks using Support Vector Machine (SVM) can faithfully predict the genotype of mice with an accuracy of 85.71%. These findings not only revealed hearing changes in Shank3B knockout autistic-like mice during development, but also suggested that hearing abnormalities could potentially be used as an early and effective indicator of ASD risk.

High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice.

Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spectrum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social deficits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-positive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunction in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.

Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism.

Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H3R/D2R/D3R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H3R/D2R/D3R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.

Treatments for Social Interaction Impairment in Animal Models of Schizophrenia: A Critical Review and Meta-analysis.

BACKGROUND: While pharmacological treatments for positive symptoms of schizophrenia are widely used, their beneficial effect on negative symptoms, particularly social impairment, is insufficiently studied. Therefore, there is an increasing interest in preclinical research of potentially beneficial treatments, with mixed results. The current review aims to evaluate the efficacy of available treatments for social deficits in different animal models of schizophrenia. STUDY DESIGN: A systematic literature search generated 145 outcomes for the measures "total time" and "number" of social interactions. Standardized mean differences (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was tested using Q statistics in a random-effect meta-analytic model. Given the vast heterogeneity in effect sizes, the animal model, treatment group, and sample size were all examined as potential moderators. STUDY RESULTS: The results showed that in almost all models, treatment significantly improved social deficit (total time: SMD = 1.24; number: SMD = 1.1). The moderator analyses discovered significant subgroup differences across models and treatment subgroups. Perinatal and adult pharmacological models showed the most substantial influence of treatments on social deficits, reflecting relative pharmacological validity. Furthermore, atypical antipsychotic drugs had the highest SMD within each model subgroup. CONCLUSIONS: Our findings indicate that the improvement in social interaction behaviors is dependent on the animal model and treatment family used. Implications for the preclinical and clinical fields are discussed.

Effects of endocannabinoid system modulation on social behaviour: A systematic review of animal studies.

There is a clear link between psychiatric disorders and social behaviour, and evidence suggests the involvement of the endocannabinoid system (ECS). A systematic review of preclinical literature was conducted using MEDLINE (PubMed) and PsychINFO databases to examine whether pharmacological and/or genetic manipulations of the ECS alter social behaviours in wildtype (WT) animals or models of social impairment (SIM). Eighty studies were included. Risk of bias (RoB) was assessed using SYRCLE's RoB tool. While some variability was evident, studies most consistently found that direct cannabinoid receptor (CBR) agonism decreased social behaviours in WT animals, while indirect CBR activation via enzyme inhibition or gene-knockout increased social behaviours. Direct and, more consistently, indirect CBR activation reversed social deficits in SIM. These CBR-mediated effects were often sex- and developmental-phase-dependent and blocked by CBR antagonism. Overall, ECS enzyme inhibition may improve social behaviour in SIM, suggesting the potential usefulness of ECS enzyme inhibition as a therapeutic approach for social deficits. Future research should endeavour to elucidate ECS status in neuropsychiatric disorders characterized by social deficits.

Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring.

Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor ß (ERß) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERß expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

Sevoflurane Ameliorates Schizophrenia in a Mouse Model and Patients: A Pre-Clinical and Clinical Feasibility Study.

BACKGROUND: GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients. METHODS: Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2. RESULTS: MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01). CONCLUSION: Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients' symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.

The mirror neuron system compensates for amygdala dysfunction - associated social deficits in individuals with higher autistic traits.

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher (n = 77) as opposed to lower (n = 79) autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed worse recognition memory for fearful faces, smaller real-life social networks, and decreased left basolateral amygdala (BLA) responses to imitation. Additionally, functional connectivity between the left BLA and the left inferior frontal gyrus (IFG) as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The left BLA-IFG connectivity significantly moderated the autistic group differences on recognition memory for fearful faces, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.

Activation of basolateral amygdala to anterior cingulate cortex circuit alleviates MK-801 induced social and cognitive deficits of schizophrenia.

Introduction: Schizophrenia is a severe psychiatric disorder with a high prevalence worldwide, however, its pathogenesis remains poorly understood. Methods and results: In this study, we used the non-competitive NMDA receptor antagonist MK-801 to induce schizophrenia-like behaviors and confirmed that mice exhibited stereotypic rotational behavior and hyperlocomotion, social interaction defects and cognitive dysfunction, similar to the clinical symptoms in patients. Here, the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) were involved in the schizophrenia-like behaviors induced by MK-801. Furthermore, we confirmed BLA sent glutamatergic projection to the ACC. Chemogenetic and optogenetic regulation of BLA-ACC projecting neurons affected social and cognitive deficits but not stereotypic rotational behavior in MK-801-treated mice. Discussion: Overall, our study revealed that the BLA-ACC circuit plays a major role and may be a potential target for treating schizophrenia-related symptoms.