Synaptic and genetic bases of impaired motor learning associated with modified activity-dependent cortical plasticity in heterozygous reeler mutants.

RELN (Reelin) is one of the genes implicated in neurodevelopmental psychiatric vulnerability. Patients with neurodevelopmental disorders show impaired motor skill learning. While neurodevelopmental disorders are considered heritable synaptic disorders with transcriptional dysregulation, we herein investigated how the effect of genetic variation on synaptic function and transcriptome profile underlie activity-dependent cortical plasticity, which supports development of fine motor skills. Heterozygous Reeler mutant (HRM) mice displayed impairments in reach-to-grasp learning, accompanied by less extensive cortical map reorganization, examined after 10 days of training by intracortical microstimulation. Assessed by patch-clamp recordings after 3 days, the training induced synaptic potentiation and increase in glutamatergic-transmission of layer III cortical neurons in wild-type mice. In contrast, the basal excitatory and inhibitory synaptic function were depressed, affected both by presynaptic and postsynaptic impairments in HRM mice; and thus, no further training-induced synaptic plasticity occurred. RNA-sequencing showed HRM exhibited substantially lower gene enrichment associated with synaptic function, receptor function and intracellular signaling, in response to 3 days of training compared to wild-type trained mice. We demonstrated motor learning impairments associated with modified activity-dependent cortical plasticity are at least partially attributed by the basal synaptic alternation as well as the lack of early activity-induced gene enrichment in HRM.