Mechanisms of olfactory signal processing

Project Summary/Abstract (ASDs) an Individuals communication, can spectrum disorders results from the loss of expression of the Fragile X mental retardation protein (FMRP), mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. with FXS can exhibit a range of debilitating deficits in cognitive abilities, social interactions and and sensory processing. Deficits in sensory processing, often observed as hypersensitivity, contribute to other deficits associated with FXS (e.g., in social interactions). The Fragile X syndrome (FXS) is the single most common monogenetic cause of autism in humans. FXS broad objective of this proposal is to examine dysfunction in the olfactory system of mouse models for Fragile X with reduced expression of the mouse gene for FMRP, Fmr1. Surprisingly, despite the overwhelming importance of olfaction for rodents, there are few studies in this sensory modality in Fmr1 KO mice. Our goals, divided across three Aims, will be: Aim 1: To test the hypothesis that Fmr1 regulates inhibitory synaptic connections in the bulb. Aim 2: To test the hypothesis that Fmr1 regulates local network activity in the bulb by controlling inhibitory synaptic connections. Aim 3. To test the hypothesis that Fmr1 regulates olfactory behavior and bulbar oscillations in awake behaving mice by controlling inhibitory synaptic connections. Our studies will utilize a variety of approaches including patch-clamp recordings in brain slices, ultrastructural analyses, behavioral experiments, and in vivo electrophysiological recordings. Mouse models will include whole-animal Fmr1 KO mice, which is the most widely used mouse model of FXS, along with conditional KO and recovery mice in which Fmr1 expression is selectively and inducibly manipulated in GAD65-expressing GABAergic interneurons. This multidisciplinary approach will enable us to identify dysfunction in olfaction that results from altered Fmr1 expression at levels ranging from single synapses to whole-animal behavior and also link the changes observed at the different levels.