Grant: Project Grant

Fragile X mental retardation syndrome (FXS) is the most common known cause of autism. Studies in the mouse model of FXS (Fmr1-KO mice) have demonstrated defects in the cerebral cortex at cellular and circuit levels. A key function of the cerebral cortex is its ability to associate external sensory information with an internal representation of the world in order to make predictions about the future. One particular type of cortical neuron, the layer 5 (L5) pyramidal neuron, is believed to be the main associative neuron integrating sensory inputs in their proximal dendrites (dendrite=the receptive surface) with contextual information at their distal dendrites. Recently, it has been shown in Fmr1-KO mice that the distal dendrites of L5 pyramidal neurons have an enhanced summation of excitatory inputs, while in our preliminary data we show that proximal dendrites of L5 pyramidal neurons from Fmr1-KO mice have a diminished summation of excitatory inputs. Hence, we hypothesize that these cellular impairments can lead to an underrepresentation of sensory information and an overrepresentation of contextual information, which alter the firing and encoding of information of L5 pyramidal neurons from Fmr1-KO mice. Hence, we will examine synaptic transmission and integration of excitatory inputs in proximal and distal dendrites of L5 pyramidal neurons from control and Fmr1-KO mice, and study the functional consequences that these defects have in the association of sensory and contextual information in the Fmr1-KO mice. Lastly, we will uncover the specific mechanisms responsible for the altered synaptic integration found in the distal and proximal dendrites of Fmr1-KO L5 pyramidal neurons. To perform this work we will use cutting edge imaging, genetic, and electrophysiological tools. Our prediction is that these defects will affect the encoding of information in single neurons and the circuit they reside on; representing one of the mayor cortical defects associated with FXS.