AMPA receptor-mediated dendrite restructuring in hippocampal neurons
During the critical period of CNS development, dendritic architecture is shaped, in part, by activity-dependent stabilization and elimination of branches. This restructuring is partly dependent on the subunit composition of glutamate receptors in a manner that is both regionally specific and temporally regulated. We used primary cultures of rodent hippocampal neurons to investigate the consequences for hippocampal dendrite development when the glutamate ?-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit composition was altered. Overexpression of the AMPAR subunits GluR1 or GluR2 differentially modified hippocampal dendrite architecture. We investigated signaling pathways known to be involved in activity-dependent circuit development as possible downstream effectors of AMPA-mediated morphogenesis. We identified extracellular signal regulated kinase (ERK) 1/2 as a potential candidate of GluR1-mediated dendrite outgrowth. We found that levels of docosahexaenoic acid (DHA) and a DHA-derived bioactive metabolite, neuroprotectin D1 (NPD1) are differentially regulated by GluR1 and GluR2. DHA, but not NPD1, induced extensive dendritic branching and outgrowth. Overexpression of 15 lipoxygenase 1 (15LOX1), the enzyme responsible for conversion of DHA to NPD1, interrupted outgrowth mediated by GluR1 overexpression. In order to investigate molecular mechanisms that regulated neural circuitry outside of the critical period of CNS development, we examined dendrite morphology across the CNS in response to chronic variable stress (CVS). We found wide-spread changes in circuits implicated in neurocognitive dysfunctions associated with chronic stress, and observed substantial dendritic plasticity in the adult brain.