A fundamental problem in neuroscience is understanding how ephemeral episodes of experience are transformed into stable changes in synaptic architecture and efficacy. The creation of such long-lasting synaptic modifications requires new protein synthesis, which in turn is regulated at both transcriptional and translational levels. Moreover, the transcriptional profile of the neuron is a function of its developmental stage - e.g. critical period - and its history of activation. A major challenge in unraveling the mechanisms of long term plasticity then is to relate both developmental timing and experience-induced neural activity to the regulation of identified molecules that play key roles in synaptic plasticity. Fragile X Syndrome (FXS) offers a portal to the heart of this problem. FXS affects about 1:4000 boys and is caused by a triplet repeat expansion and hypermethylation of the Fmr1 promoter, leading to gene silencing. The protein product of the Fmr1 gene, FMRP, plays a central role in regulating protein synthesis-dependent synaptic plasticity. Our laboratory has established in vivo and cell culture systems for the study of Fmr1 transcription and expression. We find that Fmr1 transcripts are highly abundant in the developing and adult olfactory bulb and are bi-directionally regulated by olfactory experience. Preliminary in vivo and ce|l culture studies have provided evidence for two molecular mechanisms that regulate Fmr1 transcription: the transcription factor AP-2a and the selective, developmentally-regulated epigenetic modification of the Fmr1 gene regulatory regions. In the proposed studies we will use the olfactory system together with genetic and cell culture models to elucidate the molecular logic of Fmr1 gene regulation in the intact CNS.
