Reelin haploinsufficiency affects skilled motor performance associated with suppression of training-induced gene enrichment, synaptic function and activity-dependent cortical plasticity in mice

Abstract

AbstractRELN (Reelin) is one of the genes implicated in neurodevelopmental psychiatric vulnerability. Patients with neurodevelopmental disorders can experience impairments in fine motor skills. While Reelin modulates synaptic function, whether Reelin haploinsufficiency affects activity-dependent cortical plasticity which supports development of skilled movement is unclear. Here, heterozygous Reeler mutant (HRM) and Dab1floxed/ +; Emx1-Cre mice both displayed learning improvements measured by the reach-to-grasp task, but their performance levels of the forelimb motor skill were lower, compared with controls. The level of skilled motor performance was correlated with the area of cortical representations of the trained forelimb, examined after 10 days of training. Furthermore, we hypothesized that the genetic haploinsufficiency also alters changes that occur during the early phase of the training. Examined on day 3, the training induced synaptic modifications of the layer III cortical neurons in (wild-type) WT mice, which were contributed by synaptic potentiation and increase in spontaneous action-potential driven glutamatergic-transmission. On the other hand, the basal excitatory and inhibitory synaptic function were depressed, affected both by presynaptic and postsynaptic synaptic impairments in naive HRM; and thus, no further training-induced synaptic plasticity occurred in HRM. Lastly, examined after 3 days of training, the gene enrichment observed in trained WT mice was absent in trained HRM mice. The finding suggests the Reelin haploinsufficiency alters the skilled motor function; and we propose the suppression of gene enrichment, and synaptic abnormality led by the genetic insufficiency may contribute to impede the occurrence of activity-dependent cortical plasticity.Significance StatementImpairments in fine motor skills occur in subjects with neurodevelopmental disorders. We report a mutation relevant to the neurodevelopmental disorders can impact the cortical plasticity associated with skilled motor function. In wild-type mice, the motor training induced extensive activity-dependent cortical map plasticity, synaptic modifications through synaptic potentiation and excitatory-transmission increase, as well as enrichments in certain gene expressions. On the other hand, mice with Reelin haploinsufficiency (presumed mouse model of neurodevelopmental disorders) exhibited lower level of skilled motor performance, and the underlying correlates shown in wild-type mice were found suppressed. We conclude the suppression of gene enrichment, and synaptic abnormality due to Reelin haploinsufficiency may underlie the limited development of activity-dependent cortical plasticity, contributing to impairments in motor skills.