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bioRxiv · 10.64898/2026.08.26.747425

MHC class II in dopaminergic neurons prunes GABAergic synapses in neurodevelopmental disorders

Murakami, G.·Hirasaki, M.·Hashizume, M.·Hirao, A.·Ito, R.·Hojo, Y.·Nakano, T.·Uozumi, N.·Murakoshi, T.
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Abstract

Although the brain was traditionally considered immune-privileged, recent studies show immune factors play key roles in brain function. Dysfunction of these factors is linked to neurodevelopmental disorders, but mechanisms remain unclear. Using a maternal immune activation (MIA) mouse model, we investigated immune-related genes in neurodevelopmental disorder pathogenesis. MIA mice showed increased locomotor activity and disrupted prepulse inhibition. RNA-seq and qPCR analyses revealed persistent increases in major histocompatibility complex class II (MHCII) expression and persistent decreases in GABAergic synapse-related gene expression, particularly glutamate decarboxylase (Gad) expression, in dopaminergic regions. These expressions were negatively correlated, and immunohistochemistry showed MHCII at postsynaptic GABAergic synapses on dopaminergic neurons. Patch-clamp recordings confirmed reduced mIPSC frequency in MIA mice. MHCII knockout mice showed opposite phenotypes, while MHCII overexpression in dopaminergic neurons decreased Gad expression. These results suggest MIA-induced MHCII upregulation enhances pruning of GABAergic synapses on dopaminergic neurons, leading to behavioral deficits.

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Murakami, G., Hirasaki, M., Hashizume, M., Hirao, A., Ito, R., Hojo, Y., Nakano, T., Uozumi, N., Murakoshi, T.. 2026-09-01. MHC class II in dopaminergic neurons prunes GABAergic synapses in neurodevelopmental disorders. https://doi.org/10.64898/2026.08.26.747425

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