Title

Presynaptic and postsynaptic NMDA receptors mediate distinct effects of BDNF on excitatory synaptic transmission

Date of Completion

January 2008

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

Brain-derived neurotrophic factor (BDNF) has long been known as a trophic factor involved in survival, differentiation, and maintenance of neuronal populations in the central nervous system. In addition to these effects, BDNF has emerged as a major activity-dependent regulator of synaptic transmission and plasticity in many brain areas, most notably the neocortex and hippocampus. Pre- and postsynaptic localization of BDNF and its cognate receptor, tropomyosin receptor kinase B (TrkB) at glutamate synapses in particular, make it an ideal candidate for rapidly fine-tuning excitatory transmission and modulating the ability of synapses to undergo activity-dependent plasticity. Furthermore, N-methyl-D-asparate (NMDA) receptors, which play an important role in some forms of plasticity, are a primary target of BDNF-TrkB receptor signaling. Although BDNF appears to have pre- and postsynaptic effects on glutamatergic transmission, consistent with localization of TrkB receptors to axon terminals and dendritic spines, the underlying cellular targets are unclear and it is not known whether pre- and postsynaptic modulation of BDNF occurs concurrently. Therefore, we tested the hypothesis that BDNF acts simultaneously through pre- and postsynaptic mechanisms to enhance glutamatergic transmission and investigated the role of NMDA receptors in mediating these effects. ^ Using whole-patch clamp recordings from primarily pyramidal neurons in slices of mouse visual cortex, the studies presented in this thesis demonstrate that BDNF acutely enhances presynaptic release and postsynaptic responsiveness through simultaneous effects on miniature excitatory postsynaptic currents (mEPSCs). Under low extracellular Mg2+ recording conditions, the presynaptic effect of BDNF is expressed as an increase in mEPSC frequency and the postsynaptic effect of BDNF is observed as an increase in the slow decay time 〈т2〉 of mEPSCs. Surprisingly, these effects are effectively blocked by NMDA receptor antagonists suggesting that the concurrent effects of BDNF depend on modulation of both presynaptic and postsynaptic NMDA receptors. Importantly, as presynaptic NMDA receptors represent a novel presynaptic target of BDNF-TrkB receptor signaling, we demonstrate a role for these receptors in action potential-dependent release. Collectively, our findings suggest that the simultaneous and synergistic modulation of pre- and postsynaptic NMDA receptors by BDNF may represent an important mechanism by which BDNF modulates activity-dependent plasticity. ^