β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice.

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.

β-catenin deficiency in forebrain excitatory neurons induces fear memory deficits and physiological alterations

The results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.

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

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

It is demonstrated that Cry1Δ11 mice exhibit robust repetitive behaviors, including excessive self-grooming and stereotyped rearing, which are associated with increased activity of DRD1-MSNs in the dorsolateral striatum, thereby identifying aberrant DRD1 signaling in the dorsolateral striatum as a promising target for therapeutic intervention.

Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.

TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.

NDP-MSH rescues LPS-induced neuroinflammation, synaptic deficits, and depressive-like behaviors in mice: involvement of MC1R–cAMP/PKA signaling

Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.