Fellowship in Support Q. He in Support of of Rescuing Cellular and Cognitive Deficits in FRX by Restoration of Chloride Homeostasis

Fragile X syndrome (FXS) is the most common form of inherited human mental retardation and also the single most common known cause of autism. FXS results from an expansion of a CGG repeat sequence in the 3’ untranslated region of the gene, which causes hypermethylation, transcriptional silencing, and a resultant loss of expression of the Fragile X mental retardation protein (FMRP) (1). FMRP is a multi-RNA binding protein that regulates transcription of a vast array of genes particularly those that encode synaptic proteins. This single gene mutation has provided an opportunity to model FXS in a mouse and identify the principal molecular and cellular pathways that contribute to the cognitive deficits in FXS and to use this to potentially develop targeted treatments. Postmortem studies examining cortical anatomy from both FXS patients and Fmr1 ko mice has revealed the presence of an excessive number of immature spines in the sensory cortex (2-5). Similarly examination of the dynamic properties of spines has demonstrated that there are delays in maturation and stabilization of spines (6) which correlate with delays in synaptic plasticity (7). Many of these reported alterations occur during early cortical development. There are delays in the critical period for synaptic plasticity in the sensory cortex, including the retention of silent, NMDA receptor (NMDAR) only, synapses accompanied by a parallel shift in the time window of NMDAR dependent synaptic plasticity (6). Some of these early changes could contribute to alterations in the emergent properties of the network including changes in the ‘Up states’ that contribute to oscillatory activity in the cortex which underlie cognition (8). Notably, the assembly of cortical circuits relies on the coordinated timing of multiple events that produce the precise connectivity required for the proper functioning of those networks. Alterations in the timing of these events can lead to disrupted connectivity and the emergence of cognitive and behavioral alterations. Thus the early delays in structural and functional synaptic development occurring during time-sensitive developmental windows are likely to have significant effects on the coordinated development and refinement of sensory circuits, and have been proposed to be a common feature of several neurodevelopmental disorders (9).