Guoqing Guo

Social isolation is a pervasive stressor that disrupts social cognition, yet its neural mechanisms in adulthood remain unclear. Here, we showed that four weeks of social isolation in adult male mice selectively impaired social novelty memory without affecting general sociability, object recognition, working memory, or anxiety- and depression-like behaviors. This deficit was sex-specific, as female mice remained unaffected. Mechanistically, c-Fos mapping and in vivo calcium imaging revealed that social isolation induced a maladaptive shift in prefrontal excitatory–inhibitory (E/I) balance, characterized by both exaggerated activation of medial prefrontal cortex (mPFC) glutamatergic neurons and attenuated recruitment of local GABAergic interneurons specifically during novel social exploration. Causal manipulations showed that chemogenetic or optogenetic activation of mPFC glutamatergic neurons in group-housed males was sufficient to recapitulate the social novelty memory impairment, whereas inhibition of these neurons in isolated mice rescued the deficit. At the cellular level, electrophysiological recordings demonstrated that SI enhanced the intrinsic excitability of mPFC pyramidal neurons and induced a synaptic E/I imbalance, characterized by increased excitatory and decreased inhibitory drive. Together, our findings establish that adult social isolation disrupts social novelty memory processing by shifting the mPFC excitatory-inhibitory balance toward a net hyperexcitable state, revealing a reversible, circuit-specific mechanism for isolation-induced social cognitive deficits.

The trafficking of AMPA receptors (AMPARs), including internalization, recycling, and membrane reinsertion, is critical for maintaining synaptic plasticity. Our previous work showed that the microtubule-severing protein Spastin regulates AMPAR surface expression, but the underlying mechanisms remain to be fully elucidated. Here, we demonstrate that deSUMOylated Spastin (Spastin-K427R) enhanced GluA1 recycling and membrane reinsertion and is associated with dendritic spine maturation and excitatory synaptic transmission. Overexpression of Spastin-K427R increased surface GluA1 expression, spine density, and miniature excitatory synaptic currents (mEPSC) amplitude and frequency, with stronger effects than wild-type Spastin. While wild-type Spastin directed GluA1 to both recycling and late endosomes, Spastin-K427R preferentially promoted its localization to Syntaxin 13-associated recycling endosomes and reduced LAMP1-associated degradation. We further identified IST1, an ESCRT-III complex component, as a key mediator of Spastin’s effect. Co-overexpression of IST1 with Spastin enhanced synaptic transmission and spine maturation, whereas IST1 knockdown reduced GluA1 surface levels and abolished Spastin’s effects. Notably, Spastin-K427R exhibited enhanced binding to IST1 than wild-type Spastin. These findings reveal a post-translational mechanism by which the deSUMOylation of Spastin facilitates IST1-dependent AMPAR recycling, contributing to synaptic plasticity regulation. Graphical Abstract

Circular RNAs (circRNAs), as stable and evolutionarily conserved epigenetic regulators, have attracted growing attention, especially those enriched in the central nervous system (CNS). CNS-specific circRNAs downregulated during disease progression are increasingly recognized as potential therapeutic targets. The clinical translation of circRNAs for stroke treatment further supports the feasibility of circRNA-based therapies, raising the question of whether certain circRNAs may also modulate chemotherapy-induced neuropathic pain (CINP). In this study, we report the identification of a dorsal horn–specific circRere, which is significantly downregulated following vincristine (VCR) administration. Mechanistically, circRere encodes a novel protein, cRERE, in an N6-methyladenosine (m6A)-dependent manner. cRERE alleviates CINP by spatially interfering with the phosphorylation activation site of extracellular signal-regulated kinase 1 (ERK1), thereby preventing downstream activation of the CREB/IL-1β signaling cascade. Taken together, our findings reveal that circRere exerts analgesic effects via an unconventional translation mechanism that generates a functional protein. This study highlights the therapeutic potential of targeting disease-specific downregulated circRNAs and their encoded endogenous proteins for the treatment of CINP.

Whether and how myelin plasticity, an emerging new form of brain plasticity, is involved in autism spectrum disorder (ASD) remains unknown. Here, we identify deficits in oligodendrocyte (OL) generation and myelination in the barrel cortex (BC) of the male NL3-R451C-KI mouse model of ASD. These mice also show impaired texture recognition, disrupted gamma neuronal oscillations, and reduced excitability and myelination level in the BC-PV interneuron. These abnormalities can be rescued by a promyelinating strategy and are recapitulated by genetic blockade of myelination in Myrf-cKO mice. Furthermore, OL progenitor-specific conditional NL3 knockout mice show similar deficits in BC-PV interneuron myelination and excitability, as well as neuronal oscillation and texture recognition, closely resembling the NL3-R451C-KI phenotype. Collectively, these results demonstrate that NL3 mutations commonly cause hypomyelination and reduced excitability in BC-PV interneurons, disrupting neuronal oscillation and contributing to ASD-like sensory dysfunction. Our finding reveals a mechanism underlying ASD and highlights OLs/myelin as potential therapeutic targets for ASD.

Chronic stress can lead to maladaptive neuroplastic changes in the brain, with the prefrontal cortex (PFC) being a critical site of vulnerability due to its role in executive function and emotional regulation. Extensive evidence has confirmed that chronic stress induces neuroplasticity changes at multiple scales, including functional reorganization, intrinsic neuronal excitability, and structural and synaptic plasticity. These alterations are particularly prominent in glutamatergic pyramidal neurons of the PFC and involve synaptic weakening, dendritic retraction, spine loss, and impaired long-term potentiation. The paradoxical findings regarding pyramidal neuron excitability—ranging from hyper- to hypoactivity—highlight the complex and dynamic nature of stress-induced plasticity. One proposed mechanism linking these alterations is excitotoxicity, characterized by excessive glutamate signaling, impaired astrocytic clearance, and calcium overload, ultimately leading to synaptic dysfunction and structural degeneration. Additionally, inhibitory interneurons and glial cells might also play essential roles in shaping and modulating the stress response. This review integrates findings across neuroplasticity levels to provide a comprehensive understanding of how chronic stress reshapes the PFC. We further discuss the therapeutic potential of targeting homeostatic plasticity as a compensatory mechanism and propose future directions to clarify temporal dynamics, circuit specificity, and molecular regulators underlying maladaptive neuroplasticity in stress-related disorders.