Transcriptional silencing of the Fmr1 gene encoding Fragile X mental retardation protein (FMRP) is the most common inheritable cause of mental disability, known as Fragile X syndrome (FXS). FXS is also characterized by a high co-morbidity with autism and epilepsy. Extensive research efforts have thus focused on elucidating the functions of FMRP at synapses to uncover the molecular basis of FXS. FMRP was identified as an RNA-binding protein regulating local protein synthesis in dendrites, and research to date on FXS has concentrated extensively on the translation-dependent roles of FMRP in dendritic function. Yet despite two decades of intensive studies the molecular basis of FXS remains incompletely understood. We have recently identified important functions of FMRP beyond the dendritic compartment;most notably the critical presynaptic roles of FMRP in regulating action potential (AP) waveform and synaptic transmission. Specifically, our results demonstrate that FMRP regulates neurotransmitter release in excitatory hippocampal neurons via modulation of AP duration in a cell-autonomous presynaptic manner. These presynaptic actions of FMRP are translation-independent and are mediated specifically by FMRP interaction with the large-conductance calcium-activated K+ (BK) channels. Loss of FMRP causes reduced BK channel activity and excessive AP broadening, leading in turn to elevated presynaptic calcium influx, increased neurotransmitter release and short-term plasticity (STP) during repetitive activity. Information theory-based analysis indicates that these defects associated with FMRP loss cause marked abnormalities in the ability of synapses to transmit information. Our observation that FMRP modulates AP duration both in the hippocampal and cortical pyramidal neurons suggests that BK channel-dependent regulation of presynaptic function by FMRP may be a widespread phenomenon that could play a role in the pathophysiology of FXS. Indeed, our current studies suggest that pharmacological or genetic manipulations targeting BK channel function can reduce seizure susceptibility and rescue several synaptic and behavioral deficits caused by FMRP loss. Yet the mechanisms by which FMRP modulates the activity of BK channels and the roles of FMRP-BK channel interaction in cognitive and behavioral abnormalities in FXS remain unknown. The proposed studies will span from single-channel to behavioral analyses to address these critical questions. Our results are expected to provide major new insights into pathophysiology of FXS and open new avenues for drug development and intervention.
Fragile X syndrome (FXS) is the most common heritable form of intellectual disability and the leading genetic cause of autism, yet the causes of cognitive and behavioral impairments in FXS remain incompletely understood. This proposal departs from the traditional focus of FXS research on translational regulation and investigates molecular mechanisms of abnormal neuronal excitability and neurotransmitter release in an FXS mouse model, and their implications to behavioral and cognitive deficits. By using a multifaceted approach spanning from single ion channels to behavioral assays, our studies may guide the development of new therapeutic strategies for the treatment of FXS.
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