The cytoskeleton in neuronal cell biology

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The cytoskeleton is an evolutionarily conserved structure consisting of an internal filamentous protein scaffold that controls the architectural and functional features of cells. Composed by the interconnection of microtubule filaments (MTs), actin microfilaments (MFs), intermediate filaments and their associated proteins, the cytoskeleton serves as a “highway” for intracellular transport, provides architectural support to cells and participates in cell signaling. It is particularly critical in neurons as it allows these cells to respond morphologically and functionally to depolarization. My application proposes to decipher the “structure -> function” relationship played by the cytoskeleton in neurons with a particular focus on the process of learning and memory. “Is the cytoskeleton important for learning and memory?”. “How does the cytoskeleton contribute to memory formation?” Dynamic changes underlying the maintenance of the connections (synapses) between nerve cells are thought to be responsible for the restructuring of neural networks that serve to encode behaviors including memories. Synapses are composed by a presynaptic side (i.e. axon terminal) and a post-synaptic side (i.e. spine protruding from a dendrite). Despite the fact that both sides are regulated by cytoskeleton, the role of the cytoskeleton in learning and memory is not well understood. My lab has recently generated a unique animal model that allows us to study the cytoskeleton-dependent postnatal mechanisms underlying spatial learning and memory. Our new animal model that was created by gene knockout of a particular cytoskeletal protein, develops normally. Importantly, the mutants exhibit profound spatial learning deficits 7 weeks after birth. Ultra-structural studies revealed early cytoskeletal abnormalities in dendrites of pyramidal excitatory neurons in the CA1 region of the hippocampus, a key brain area implicated in learning and memory. Genome-wide transcriptome profiling of hippocampi of the mutant animals revealed deregulation of cell adhesion and cytoskeletal genes involved in neuronal plasticity. Here, I propose 1) to determine whether deregulation of the cytoskeleton in pyramidal excitatory neurons affects the biology of neighbor inhibitory interneurons, as well as the interface between the two cell types, thereby altering the neural network, 2) to validate cell adhesion and cell-cell communications proteins identified from the transcriptome analysis that modulate the activity between these cell types and determine how it relates to the cytoskeleton in pyramidal neurons, and 3) to address the non-cell autonomous functions of cytoskeletal proteins, a topic that is not covered in the current literature. The experiments will allow us to understand how the cytoskeleton impacts cell-cell communication and preserve neuronal networks in the postnatal brain during learning and memory.