Increased activity of DRD1-MSNs in dorsolateral striatum underlies Cry1Δ11 mutation-induced repetitive behaviors.

Deletion of Bmal1 in the Prelimbic Cortex Glutamatergic Neurons Triggers Schizophrenia-Like Behaviors in Mice.

Left BLP to dmPFC circuit dysfunction underlies autism-like behaviors induced by prenatal and lactational Bisphenol S exposure.

Environmental factors are increasingly implicated in autism spectrum disorder (ASD), and this study investigated whether bisphenol S (BPS), a widely used endocrine disruptor, induces autism-like phenotypes using mouse and neuronal models. Prenatal and lactational BPS exposure induced male-biased autism-like behaviors, including impaired sociability, increased repetitive behaviors, and anxiety-related alterations. These behavioral deficits were accompanied by prefrontal BPS accumulation, reduced regional homogeneity and c-Fos-positive neuronal activation in the left dorsomedial prefrontal cortex (dmPFC), and persistent synaptic abnormalities. Chemogenetic manipulation demonstrated that dmPFC activity is critical for the core social-deficit domain of BPS-induced autism-like behaviors, and that dmPFC activation alleviated these deficits. Further investigation via rs-fMRI and whole-brain monosynaptic retrograde tracing revealed weakened functional and anatomical connectivity between the left posterior basolateral amygdaloid nucleus (BLP) and dmPFC. This was associated with reduced CaMKIIα-positive excitatory neuronal phenotype and altered excitatory/inhibitory (E/I) marker profiles in the left BLP. Targeted activation of excitatory BLP-dmPFC projections ameliorated the core social deficits within BPS-induced autism-like behaviors. Collectively, our findings indicate that prenatal and lactational BPS exposure induces autism-like behaviors by disrupting the left BLP-dmPFC circuit, accompanied by altered E/I marker profiles and synaptic abnormalities. These findings establish a neural circuit basis for BPS-related neurodevelopmental toxicity.

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.

Age-dependent reorganization of behavioral and striatal function in Cntnap2 knockout mice.

It is demonstrated that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features.

ERK-dependent hyperexcitability of BLA neurons projecting to dCA3 underlies social dysfunction in a male mouse model of fragile X syndrome.

BACKGROUND Social dysfunction is a core symptom of autism spectrum disorder (ASD), including fragile X syndrome (FXS), but its underlying neural circuits and molecular mechanisms remain poorly understood. Previous studies have implicated the amygdala and hippocampus in social behaviour, yet the specific pathways and signalling events linking genetic deficits to behavioural dysfunction have not been fully delineated. METHODS Using activity-dependent c-Fos mapping, fibre photometry, closed-loop optogenetics, pharmacological inhibition, and shRNA-mediated knockdown, we investigated the role of the BLA-dCA3 projection and ERK signalling in male Fmr1 KO mice, complemented by re-analysis of human ASD snRNA-seq data and whole-cell patch-clamp recordings. FINDINGS We found that BLA-dCA3 projecting neurons are aberrantly hyperactivated in Fmr1 KO mice during interactions with both novel and familiar mice, and that closed-loop activation of this pathway in WT mice during familiar interaction impairs social discrimination, whereas its inhibition in KO mice rescues the deficit. Additionally, ERK signalling is upregulated in the BLA of both patients with ASD and Fmr1 KO mice; knocking down FMR1 in the adult BLA recapitulates both the social deficit and ERK hyperactivation, while pharmacological ERK inhibition rescues social behaviour and normalises neuronal hyperexcitability. INTERPRETATION These findings pinpoint the BLA-dCA3 circuit and BLA-specific ERK signalling as critical mediators of social discrimination deficits in FXS. Our study establishes a causal link from FMRP loss to circuit dysfunction and ERK pathway dysregulation, and suggests that targeting this pathway may offer a promising strategy for treating social dysfunction in ASD and FXS. FUNDING This work was supported by grants from the National Science and Technology Major Project (2025ZD0214701), the National Natural Science Foundation of China (32171014, 31970940, and 32500889), Nanhu Brain-Computer Interface Institute (010904018), and the Zhejiang Provincial Natural Science Foundation of China (LMS25C090004).

Shank3b deficiency drives anxiety-like behaviors via impaired GABAergic inhibition and enhanced intrinsic excitability in the basolateral amygdala.

Anxiety is a highly prevalent and disabling comorbidity in autism spectrum disorder (ASD), but its neurobiological mechanisms remain poorly understood. The basolateral amygdala (BLA) is critically involved in anxiety processing, yet the synaptic substrates linking ASD gene mutations to BLA dysfunction are not fully defined. Here, we evaluated anxiety-like behaviors in male Shank3b knockout (Shank3b-/-) mice using open field, elevated plus maze, and light-dark transition tests. Molecular alterations in the BLA were assessed by qPCR and Western blotting, and whole-cell patch-clamp recordings were performed to examine synaptic transmission and intrinsic excitability of BLA pyramidal neurons. Shank3b-/- mice exhibited robust anxiety-like behaviors across multiple behavioral paradigms. In the BLA, expression of the GABAA receptor α2 subunit (GABRA2) was significantly reduced, accompanied by decreased levels of NMDA receptor subunits (GluN2A and GluN2B). Electrophysiological recordings revealed a marked reduction in inhibitory synaptic transmission, as evidenced by decreased frequency and amplitude of spontaneous inhibitory postsynaptic currents, whereas excitatory transmission remained largely unchanged, resulting in a significantly elevated excitation/inhibition (E/I) ratio. In addition, BLA pyramidal neurons displayed increased intrinsic excitability, characterized by a depolarized resting membrane potential and enhanced action potential firing. Collectively, these findings identify impaired GABAergic transmission associated with reduced GABRA2 expression as a key mechanism underlying E/I imbalance and heightened neuronal excitability in the BLA of Shank3b-deficient mice, which likely contributes to ASD-related anxiety-like behaviors. These results identify GABAA receptor signaling as a promising therapeutic target for pharmacological intervention in ASD-related anxiety.