Pathological plasticity in fragile X syndrome

Abstract

Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.

Figure 1

General model of effective plasticity in wild-type versus Fmr1 KO mice. In primary somatosensory cortex of wild-type mice the capacity for effective plasticity increases rapidly from birth, peaking during the critical period of network development and then normalizing into adulthood. Fmr1 KO mice display a delay in the increased expression of plasticity mechanisms [103] that normalizes at approximately the same developmental time point as wild-type mice [103, 123]. However, persistent deficiencies in plasticity such as dentritic spine dynamics [122] compromise effective plasticity throughout network development in Fmr1 KO mice.