Molecular mechanisms of neurite growth with AMPA receptor potentiation.

Positive allosteric modulation of AMPA receptor function has therapeutic potential in a number of psychiatric disorders and neurodegenerative diseases. AMPA receptor potentiators can induce neurite sprouting in vivo. Using a strategy of combined morphological and biochemical analyses, we investigated the effect of the AMPA receptor potentiator LY404187 on neurite growth in the SH-SY5Y human neuroblastoma cell line. LY404187 (0.1-10 microM) increased average neurite length and neurofilament expression when co-administered with s-AMPA. Co-incubation with s-AMPA and LY404187 also increased Trk receptor expression. All actions of LY404187 were sensitive to AMPA receptor blockade by the selective antagonist CNQX (10 microM). Antibody sequestration of BDNF attenuated neurite growth following AMPA receptor potentiator administration, suggesting that LY404187 increases neurite length in vitro by a BDNF mediated mechanism. AMPA receptor potentiation activates multiple intracellular neurochemical cascades and the present report identifies BDNF as one key mediator of the neurotrophic effects of AMPA receptor potentiation.