Signal transduction mechanisms that regulate the development and structural plasticity of excitatory synapses

Activity and experience-dependent and independent alterations of the strength and structure of individual synapses contribute to the formation of neural circuits during brain development and underlie storage and processing of information in the brain. These functional and structural changes of synapses, collectively referred to as synaptic plasticity, are essential for many aspects of behavior, including learning and memory.

Dendritic spines are tiny protrusions of dendrites and are the sites of most excitatory synapses in the brain. They represent the postsynaptic compartment of excitatory synapses and contain the machinery required for plasticity. Spines control synaptic function by providing chemical compartmentalization, which is important for input-specific plasticity, and confer dendrites the ability to actively participate in synapse formation. Changes in the number, structure, and protein composition of spines in the developing and adult brain have been of great interest recently because they are essential for brain wiring, neural circuit formation and refinement, and experience-dependent plasticity. Moreover, defects of spine plasticity are associated with mental retardation, autism, drug addiction, neurological disorders and mental illness.

Our laboratory is interested in the molecular mechanisms that regulate the development and structural plasticity of excitatory synapses. We focus on signal transduction mechanisms which link synaptic receptors, such as those for neurotransmitters (glutamate, serotonin, dopamine), trans-synaptic signaling and adhesion molecules (ephrins and their Eph receptors, cadherins), and growth factors, to the actin cytoskeleton. Central regulators of these pathways are small GTPases related to Ras (Ras, Rap, Rac, Rho).

Some of these signaling mechanisms are important in synapse formation and maturation. One such signaling pathway we discovered starts with the activation of postsynaptic EphB receptors by their presynaptic ligands, B-type ephrins. EphB activation induces phosphorylation and plasma membrane recruitment of the brain-specific Rac guanine-nucleotide exchange factor kalirin. Kalirin activates Rac, which in turn activates PAK kinase, and ultimately regulates actin cytoskeletal rearrangements that result in spine proliferation and maturation.

Activity-dependent structural changes in synapse are important for circuit refinement during development and in structural encoding of information. We recently discovered a signal transduction pathway that regulates activity-dependent structural changes in spines and coordinates them with glutamate receptor content and potentially with synapse function. This signaling cascade is initiated by the activation of synaptic NMDA-type glutamate receptors which results in the activation of the small GTPase Rap. Rap acts as a bimodal molecular switch that coordinates synaptic structure and function: activated Rap induces spine neck elongation and a reduction of AMPA-type glutamate receptors in these spines; inactivation of Rap results in the formation of large spines rich in AMPA receptors. The effects of activated Rap on spine structure are mediated by the recruitment of the PDZ domain-containing protein AF-6/afadin to the plasma membrane.

Our long-term goal is to discover novel synaptic signaling mechanisms, and to evaluate their role in controlling neuronal form and function, neural circuit formation and function, and behavior and cognition. Such mechanisms are also likely to be associated with drug addiction, neuropsychiatric disorders (schizophrenia, depression, Alzheimer’s disease, eplilepsy, HIV encephalitis) and neurodevelopmental disorders (mental retardation, autism, Rett syndrome, Down syndrome), and could yield potential targets for treatments of these conditions.

We employ molecular, biochemical and cell biological methods, confocal microscopy and time-lapse imaging of neurons, and genetic approaches to identify and characterize novel molecular mechanisms of synapse development and structural plasticity.