Altered medial prefrontal-striatal connectivity and plasticity in humanized CBLN2 mice

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ID: 337775
2026
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Abstract
Abstract Deciphering processes that are responsible for differences in brain development and architecture among species may provide clues to the species-specific program and may facilitate a mechanistic understanding of vulnerability to neuropsychiatric disorders. It has recently been shown that the promoter of the CBLN2 gene, which codes for a synaptogenic factor, cerebellin 2 (Cbln2), has a repressor element in mice but not in humans. A humanized mouse lacking this repressor (hCbln2) reproduces higher spine density in medial prefrontal cortex (mPFC) neurons and higher corticothalamic connectivity observed in humans. Cbln2 is part of a trans-synaptic complex that includes glutamate delta-1 receptor (GluD1) and neurexins (Nrxn) (GluD1-Cbln2-Nrxn). Interestingly, we have previously reported a contrasting striatal patch-matrix expression pattern of GluD1 in mouse versus monkey, suggesting a potential role of the GluD1-Cbln complex in species differences. In this study, we examined the synaptic organization and function in the cortex and dorsal striatum of hCbln2 mice. Consistent with previous reports, hCbln2 mice exhibited increased vGluT1 expression in the mPFC, indicating enhanced intracortical connectivity. Electrophysiological recordings further revealed an increased mEPSC frequency along with a reduced mIPSC frequency in layer 2/3 pyramidal neurons, suggesting an increase in excitatory/inhibitory balance. These changes were accompanied by enhanced mTOR signalling and autophagic deficits in the mPFC. Contrasting synaptic changes were observed in the striatum with an increase in vGluT2 and a reduction in vGluT1, together with a decrease in GluD1-Cbln1 and an increase in hevin. Importantly, corticostriatal dysfunction characterized by a reduction in cortical contribution to mEPSCs and impaired DHPG-induced synaptic depression was observed in the hCbln2 medium spiny neurons. Further, hCbln2 mice displayed increased repetitive behaviour together with social and affective-like deficits, consistent with autism-relevant phenotypes. Collectively, these findings identify humanized Cbln2 regulation as a driver of divergent cortical and striatal synaptic remodelling, disrupted corticostriatal synaptic function, and behavioural abnormalities relevant to neurodevelopmental disorders.
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Authors Kishore Kumar S. Narasimhan, Poojashree B. Chettiar, Siddhesh S. Sabnis, Phani Kumar Kola, Shriti S Thakur, Gajanan P. Shelkar, Devansh G. Asati, Dinesh Yugraj Gawande, Shrihari R Jadhav, Shashank Manohar Dravid
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Journal Brain research
Year 2026
DOI
10.1093/brain/awag376
URL
https://doi.org/10.1093/brain/awag376
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