Neurotrophin signaling modulates CNS synaptogenesis

Synapse formation in the central nervous system is a complex process that involves the dynamic interplay of numerous signals exchanged between pre- and postsynaptic neurons as well as perisynaptic glia. In recent decades, members of the neurotrophin family, which are widely expressed in the developing and mature central nervous system and are well known for their roles in promoting neuronal survival and differentiation, have emerged as key modulators of synaptic architecture and neural transmission. While the list of neurotrophin functions in neural development continues to grow, the precise mechanisms by which neurotrophins modulate synapse formation and maturation are currently unknown.; In my thesis work, I have examined the role of neurotrophins in CNS synaptogenesis by studying the development of excitatory and inhibitory hippocampal synapses in vitro. First, I have identified a role for postsynaptic TrkB signaling in modulating NMDA and GABAA receptor cluster formation and maintenance at central synapses, and have demonstrated that neurotrophin signaling coordinately modulates these receptors as part of mechanism that promotes the balance between excitation and inhibition in developing circuits. Second, I provide evidence that astrocytes promote the formation of GABAergic synapses in vitro by differentially regulating the development of inhibitory presynaptic terminals and postsynaptic GABAA receptor clusters, and that glial modulation of inhibitory synaptogenesis is mediated by neurotrophin-dependent and -independent signaling. As part of this work, I demonstrate that astrocytes influence the stability of inhibitory synapses by dynamically regulating GABAA receptor recruitment to and withdrawal from postsynaptic sites via the opposing actions of BDNF and NT3 signaling. Together, these findings extend our understanding of how neuronal-glial communication modulates the formation, maintenance and function of central synapses and set the stage for defining the cellular and molecular mechanisms by which neurotrophins direct synaptogenesis within the developing brain.