Project 462423

The fundamental operation of any neuron is to integrate synaptic inputs in order to decide when to fire an action potential. However, how neurons integrate thousands of inputs in order to make this decision is still unclear. Further, the presence of dendritic spines, the postsynaptic side of most excitatory synapses, on pyramidal neurons complicates the problem of understanding synaptic integration as the role of spines in the processing, storage and computing of excitatory inputs remains ill-defined. In this proposal, I plan to address the following aims: 1) unravel the molecular and biophysical basis of excitatory synaptic transmission in single spines, 2) determine the molecular and biophysical mechanisms by which spines can store information and 3) uncover how this finely tuned interplay between passive and active biophysical and molecular spine mechanisms control the input/output properties of neocortical pyramidal neurons. I will take multifaceted in vitro and in vivo approaches to tackle these aims using molecular, electrophysiological, structural and genetic techniques. I expect that these experiments will shed light on the understanding of the role of spines in excitatory synaptic transmission and storage and to the development of novel therapeutic approaches for neurodegenerative disorders like Alzheimer disease and fragile X syndrome, illnesses where spine structure and function is impaired.