NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity.
Journal Article (Journal Article)
NMDA receptor antagonists produce region-specific neurodegeneration by an undetermined mechanism, but one proposed mechanism involves disinhibition. In certain areas of the brain, NMDA receptors mediate excitatory drive onto inhibitory interneurons. Thus, NMDA receptor/channel antagonists may reduce inhibition (i.e., produce "disinhibition"). If a sufficient level of disinhibition is produced, enhanced vulnerability to excitotoxicity may result. Furthermore, if there are region-specific differences in NMDA antagonist-induced disinhibition, this could underlie region-specific NMDA antagonist-induced neurotoxicity. In the present study, we tested this hypothesis by exposing rat brain slices to the NMDA receptor antagonist dizocilpine maleate (MK-801) and measuring MK-801-induced disinhibition in areas of higher and lower vulnerability to neurodegeneration [posterior cingulate/retrosplenial cortices (PCC/RSC) and parietal cortex, respectively]. Using whole-cell patch-clamp techniques, bicuculline-sensitive GABA(A) receptor-mediated IPSCs were measured in biocytin-labeled pyramidal neurons in the PCC/RSC and parietal cortex. In the PCC/RSC, bath-applied MK-801 (10-40 microm) produced disinhibition, shown as a concentration-dependent decrease in spontaneous IPSC frequency and amplitude; MK-801 (40 microm) also reduced evoked IPSC amplitudes. In parietal cortex, MK-801 produced significantly less disinhibition. To determine whether disinhibition is caused by presynaptic or postsynaptic mechanisms, we tested the effects of MK-801 (40 microm) against miniature IPSC (mIPSC) frequency and amplitude in tetrodotoxin (TTX; 0.5 microm)-treated slices and found that MK-801 did not alter mIPSC frequency or amplitude. Taken together, these results suggest that NMDA receptors regulate activity of inhibitory interneurons and, consequently, GABA release in certain cortical areas. This region-specific reduction in inhibitory input to pyramidal cells could underlie the region-specific neurotoxicity of NMDA antagonists.
Full Text
Duke Authors
Cited Authors
- Li, Q; Clark, S; Lewis, DV; Wilson, WA
Published Date
- April 15, 2002
Published In
Volume / Issue
- 22 / 8
Start / End Page
- 3070 - 3080
PubMed ID
- 11943810
Pubmed Central ID
- PMC6757533
Electronic International Standard Serial Number (EISSN)
- 1529-2401
Language
- eng
Conference Location
- United States