As a key component of the cytoskeleton, microtubule dynamics provide structural support for neurite growth. Spastin plays a critical role in reshaping microtubule arrangement, which is essential for axon development and regeneration. However, the mechanism by which spastin is activated and functions remains unclear. In this study, we discovered that phosphorylation of spastin at Ser210 promotes dendrite growth and surface expression of GluA1 in neurons, enhancing synaptic transmission. Conversely, dephosphorylation of spastin inhibits dendrite growth and surface expression of GluA1, weakening synaptic transmission. PTEN interacts with the MIT domain of spastin through its C-terminal region, resulting in reduced spastin phosphorylation expression levels. This process suppresses the transport of the AMPA receptor GluA1 subunit, thereby modulating neurite outgrowth and weakening synaptic transmission. In conclusion, our research indicates that PTEN is the pathway that regulates the phosphorylation of spastin, providing an important reference for the treatment of neurological diseases characterized by microtubule dysregulation.
Danlei Liu, Jiagui Zhong, Laijian Wang et al.· ACS Chemical Neuroscience· 0 citations
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.
Quan Yuan, Bingyu Ren, Laijian Wang et al.· Translational Psychiatry· 0 citations
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