NMDA and AMPA/Kainate Glutamate Receptors Modulate Dentate Neurogenesis and CA3 Synapsin-I in Normal and Ischemic Hippocampus

Abstract

The effect of N-methyl-D-aspartate (NMDA) and 2-(aminomethyl)phenylacetic acid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferation 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 antagonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subgranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After global ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramidal neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increased 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 death 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 moleculare of CA3 at 7 and 15 days after global ischemia was blocked by pretreatment with systemic or intrahippocampal MK-801 or NBQX. It is proposed that decreased dentate glutamate receptor activation--produced by glutamate receptor antagonists in normal animals and by chronic ischemic hippocampal injury--may trigger dentate neurogenesis and synaptogenesis. The synapsin-I induction in mossy fiber terminals most likely represents re-modeling of dentate granule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may contribute to memory recovery after hippocampal injury caused by global ischemia.

FGF-2 regulation of neurogenesis in adult hippocampus after brain injury

“…Both types of injury up-regulate neurogenesis, with a greater increase in the BrdUrd-positive cells in the hippocampus after kainic acid treatment as compared with cerebral ischemia. In fact, inhibition of excitatory amino acid receptors can decrease cell proliferation in the dentate gyrus during ischemia (50). On the other hand, cell death may be one of the triggering factors for neurogenesis (51).…”

Neural stem cells and the regulation of neurogenesis in the adult hippocampus

“…Accordingly, ovariectomy decreases proliferation, and estrogens increase neurogenesis in the dentate gyrus [19]. In the afternoon of the proestrus there is an increase of GFAP immunoreactivity specifically in dentate gyrus astrocytes but not in the number of astrocytes [43].…”

“…Proliferation in the SGL is also increased during the afternoon of proestrus in the rat, when estrogens levels are at their highest [19]. Accordingly, ovariectomy decreases proliferation, and estrogens increase neurogenesis in the dentate gyrus [19].…”

“…As reviewed above, proliferation and neuronal recruitment in the adult dentate gyrus can be altered by adrenal steroids [15,28], the blockade of NMDA receptors [33], estrogen [19], seizures [17,20], ischemia [18], serotonin [23], opiate [24] and lithium administration [25]. Although all these treatments probably have different modes of action, they may all result in changes in granule neuron activity and/or their extracellular microenvironment within the GCL, which in turn may alter the proliferation of neuronal precursors in the SGL.…”

“…Recent work in the hippocampus indicates that new neurons are derived from dividing dentate gyrus radial astrocytes [14]. Several other studies have described experimental interventions that affect proliferation, recruitment and incorporation of new neurons in the adult dentate gyrus [15][16][17][18][19][20][21][22][23][24][25]. Those studies, however, were done before the primary progenitors in the adult hippocampus were identified and could not link effects on proliferation, generation and survival of new neurons to possible alterations in the behavior of the stem cells.…”