Activity-dependent modulation of hippocampal NMDA receptors by BDNF

In the nearly 40 years following the discovery of nerve growth factor (NGF), neurotrophins (NTs) were studied as target-derived, retrograde-acting factors that governed the survival and differentiation of neurons. Investigations into the protective influences of NTs during neuropathological events such as epilepsy have revealed that some NTs are regulated at the genomic and protein levels by neural activity, thus suggesting a causal relationship between synaptic input and neurotrophin expression. An entirely new conceptual approach to NTs emerged with the discovery that they rapidly modulate synaptic efficacy with particularly compelling evidence coming from studies of brain-derived neurotrophic factor (BDNF). BDNF dynamically modulates synaptic function in multiple tissue preparations, by affecting both basal transmission as well as activity-dependent synaptic plasticity. Evidence suggests that BDNF regulation of synaptic plasticity occurs over an extremely broad developmental range, from fetal to adult neurons, suggesting roles from the refinement of synaptic connectivity to learning and memory. In the mammalian central nervous system, maturation of glutamatergic synaptic connections occurs by the selective stabilization of active synapses and elimination of inactive synapses in a process that implicates both BDNF as well as the NMDA subtype of glutamatergic neurotransmitter receptor. In this dissertation, I provide a model of enhanced synaptic efficacy, and thus re-enforced stability, of active synapses through the modulation of NMDA receptors by BDNF.