NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus

The effect of N-methyl-D-aspartate (NMDA) and 2-(aminomethyl)phenylacetic a cid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferatio n and hippocampal synapsin-I induction was examined after global ischemia. Cell proliferation was assessed using BrdU labeling, and synaptic responses were assessed using synapsin-I expression. Systemic glutamate receptor ant agonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subg ranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After g lobal ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramida l neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increa sed dramatically (>1000%, P < 0.0001). Systemic injections of MK801 or NBQX , as well as intrahippocampal injections of either drug, when given at the time of ischemia completely blocked the birth of cells in the SGZ and the d eath of CA1 pyramidal neurons at 15 days after ischemia. Glutamate receptor antagonists had little effect on cell birth and death when administered 7 days after ischemia. The induction of synapsin-I protein in stratum molecul are of CA3 at 7 and 15 days after global ischemia was blocked by pretreatme nt with systemic or intrahippocampal MK-801 or NBQX. It is proposed that de creased dentate glutamate receptor activation-produced by glutamate recepto r antagonists in normal animals and by chronic ischemic hippocampal injury- may trigger dentate neurogenesis and synaptogenesis. The synapsin-I inducti on in mossy fiber terminals most likely represents re-modeling of dentate g anule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may c ontribute to memory recovery after hippocampal injury caused by global isch emia.