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The Journal of Neuroscience, March 10, 2004, 24(10):2380-2393; doi:10.1523/JNEUROSCI.4112-03.2004
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Development/Plasticity/Repair
Postsynaptic TrkB-Mediated Signaling Modulates Excitatory and Inhibitory Neurotransmitter Receptor Clustering at Hippocampal Synapses
Sarina B. Elmariah,1 Mark A. Crumling,2 Thomas D. Parsons,2 andRita J. Balice-Gordon1 1Department of Neuroscience, University of Pennsylvania School of Medicine, and 2Department of Clinical Science, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104
Tyrosine receptor kinase B (TrkB)-mediated signaling modulates synaptic structure and strength in hippocampal and other neurons, but the underlying mechanisms are poorly understood. Full-length and truncated TrkB are diffusely distributed throughout the dendrites and soma of rat hippocampal neurons grown in vitro. Manipulation of TrkB-mediated signaling resulted in dramatic changes in the number and synaptic localization of postsynaptic NMDA receptor (NMDAR) and GABAA receptor (GABAAR) clusters. BDNF treatment resulted in an increase in the number of NMDAR and GABAAR clusters and increased the proportion of clusters apposed to presynaptic terminals. Downregulation of TrkB signaling resulted in a decrease in receptor cluster number and synaptic localization. Examination of the time course of the effects of BDNF on receptor clusters showed that the increase in GABAAR clusters preceded the increase in NMDAR clusters by at least 12 hr. Moreover, the TrkB-mediated effects on NMDAR clusters were dependent on GABAAR activation. Although TTX, APV, and CNQX treatment had no effect, blockade of GABAARs with bicuculline abolished the BDNF-mediated increase in NMDAR cluster number and synaptic localization. In contrast, application of exogenous GABA prevented the decrease in NMDAR clusters induced by BDNF scavenging. Together, these results suggest that TrkB-mediated signaling modulates the clustering of postsynaptic GABAARs and that receptor activity is required for a subsequent upregulation of NMDAR clusters. Therefore, TrkB-mediated effects on postsynaptic neurotransmitter clusters may be part of a mechanism that balances inhibitory and excitatory synaptic transmission in developing neural circuits.
Key words: neurotrophin; TrkB; NMDA receptor; GABAA receptor; activity; synapse formation
Received June 2, 2003; revised January 5, 2004; accepted January 6, 2004.
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