Brain-derived neurotrophic factor regulates the expression of AMPA receptor proteins in neocortical neurons

The role of the neurotrophins; nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5, in synaptic development and plasticity has been extensively investigated. The neurotrophins regulate synaptic transmission as well as neural development in the brain. However, the mechanisms underlying these processes are unknown. In this study we show that brain-derived neurotrophic factor triggers an increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (GluR) proteins without significant changes in their messenger RNA levels. Brain-derived neurotrophic factor treatment specifically increased the protein levels of GluR1 (193+/-22%) and GluR2/3 (182+/-11%) in cultured rat neocortical neurons. In contrast, nerve growth factor and neurotrophin-3 failed to alter the protein levels of these neurons, and brain-derived neurotrophic factor effects on N-methyl-D-aspartate-type glutamate receptors were either modest or negligible. Immunocytochemical studies indicated that the increase in AMPA receptor proteins reflects the induction of their neuronal expression, but not selective neuronal survival. In agreement with these results, cortical neurons from brain-derived neurotrophic factor-knockout mice exhibited a reduction in AMPA receptor proteins in the cytoskeletal fraction containing postsynaptic proteins. Thus, the neurotrophin plays a crucial role in modulating the expression of AMPA receptors presumably at translational or post-translation levels and is implicated in synaptic development and plasticity.