Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments may result from saturation of the plasticity mechanism making it unavailable to be recruited at the appropriate synapses to support learning (Nguyen-Vu et al., 2017). This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-K(b) and H2-D(b) (MHCI K(b)D(b−/−)), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here we extend this work by testing predictions of the saturation hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on an oculomotor learning task in which PF-Purkinje cell LTD has been implicated, with no impairment on an LTD-independent oculomotor learning task. Consistent with the saturation hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI K(b)D(b−/−)mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficit in L7-Fmr1 KO mice. These results support the hypothesis that the enhancement of synaptic plasticity can lead to its saturation in vivo and inability to support learning, providing a novel mechanistic perspective that could inform the development of new clinical approaches for autism and other disorders of the nervous system.