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bioRxiv · 10.1101/2021.06.25.449490

FMRP regulates experience-dependent maturation of callosal synaptic connections and bilateral cortical synchrony

Zhang, Z.·Rumschlag, J.·Jonak, C. R.·Binder, D. K.·Razak, K. A.·Gibson, J. R.·Huber, K. M.
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Abstract

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

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Zhang, Z., Rumschlag, J., Jonak, C. R., Binder, D. K., Razak, K. A., Gibson, J. R., Huber, K. M.. 2021-06-25. FMRP regulates experience-dependent maturation of callosal synaptic connections and bilateral cortical synchrony. https://doi.org/10.1101/2021.06.25.449490

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