Abstract
The hippocampus is a complex network tightly regulated by interactions between excitatory and inhibitory neurons. In neurodegenerative disorders where cognitive functions such as learning and memory are impaired this excitation-inhibition balance may be altered. Interestingly, the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine, currently in clinical use for the treatment of Alzheimer’s disease, may alter the excitation-inhibition balance in the hippocampus. However, the specific mechanism by which memantine exerts this action is not clear. To better elucidate the effect of memantine on hippocampal circuitry, we studied its pharmacology on NMDAR currents in both pyramidal cells (PCs) and interneurons (Ints) in the CA1 region of the hippocampus. Applying whole-cell patch-clamp methodology to acute rat hippocampal slices, we report that memantine antagonism is more robust in PCs than in Ints. Using specific NMDAR subunit antagonists, we determined that this selective antagonism of memantine is attributable to specific differences in the molecular make-up of the NMDARs in excitatory and inhibitory neurons. These findings offer new insight into the mechanism of action and therapeutic potential of NMDA receptor pharmacology in modulating hippocampal excitability.
Highlights
While the pathogenesis of neurodegenerative diseases remains poorly understood, the involvement of the glutamatergic system and, of the N -methyl-d-aspartate receptor (NMDAR) in the pathogenesis of numerous neurodegenerative disorders is widely recognized (Hardingham and Bading, 2010).N -Methyl-d-aspartate receptor are heteromultimeric channels comprised of three different subunit families (NR1, NR2A-D, NR3A-B; Meguro et al, 1992; Monyer et al, 1992; Dingledine et al, 1999)
Ca2+ influx through the NMDAR is responsible for the persistent changes observed in long-term potentiation (LTP), the cellular mechanism underlying synaptic plasticity (Nicoll and Malenka, 1999; Cull-Candy et al, 2001), which is implicated in cognitive functions such as learning and memory
We found that memantine antagonism of NMDAR currents was more robust in pyramidal cells (PCs) than in Ints at low concentrations (0.1–1 μM), while it was comparable at concentrations higher than 1 μM
Summary
N -Methyl-d-aspartate receptor are heteromultimeric channels comprised of three different subunit families (NR1, NR2A-D, NR3A-B; Meguro et al, 1992; Monyer et al, 1992; Dingledine et al, 1999) Different combinations of these subunits confer the pharmacological profile, gating properties, and Mg2+ sensitivity to the NMDAR complex (Sucher et al, 1995; Danysz and Parsons, 1998). Because of their properties, NMDARs are important to fast synaptic neurotransmission and synaptic plasticity (Cull-Candy et al, 2001). Ca2+ influx through the NMDAR is responsible for the persistent changes observed in long-term potentiation (LTP), the cellular mechanism underlying synaptic plasticity (Nicoll and Malenka, 1999; Cull-Candy et al, 2001), which is implicated in cognitive functions such as learning and memory
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