Evidence relating human verbal memory to hippocampal N -methyl- d- aspartate receptors

Abstract

Studies in rodents and nonhuman primates have linked the activity of N-methyl-D-aspartate (NMDA) receptors within the hippocampus to animals' performance on memory-related tasks. However, whether these receptors are similarly essential for human memory is still an open question. Here we present evidence suggesting that hippocampal NMDA receptors, most likely within the CA1 region, do participate in human verbal memory processes. Words elicit a negative event-related potential (ERP) peaking around 400 ms within the anterior mesial temporal lobe (AMTL-N400). Ketamine, an NMDA-receptor antagonist, reduces the amplitude of the AMTL-N400 (in contrast to other hippocampal potentials) on initial presentation, eliminates the typical AMTL-N400 amplitude reduction with repetition, and leads to significant memory impairment. Of the various hippocampal subfields, only the density of CA1 neurons correlates with the word-related ERPs that are reduced by ketamine. Altogether, our behavioral, anatomical, and electrophysiological results indicate that hippocampal NMDA receptors are involved in human memory. L ong-term potentiation (LTP) is a long-lasting increase in synaptic efficacy after high-frequency stimulation of afferent fibers. It depends on high levels of postsynaptic calcium. The primary source of the calcium influx during the induction of hippocampal LTP occurs through an ion channel that is coupled to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (1, 2). NMDA receptors are thus hypothesized to play a crucial role in the induction of associative LTP within the hippocampal CA1-region (3); this is viewed as a putative mechanism for Hebbian learning. This form of synaptic plasticity has been offered as a cellular model of memory processes in hippocampal slice preparations (4). Numerous studies in rodents and primates have linked hippocampal LTP with spatial learning and memory (5) although there are some contradictory results (6).NMDA receptors are also abundant within the human hippocampus (14, 15). NMDA receptor antagonists block LTP induction in surgically resected specimens from the human temporal cortex (16). The human mesial temporal lobe system is considered essential for declarative memory (7, 8), contributing to both encoding and retrieval (9-13). Despite the suggestive findings of animal studies, however, the question of whether hippocampal NMDA receptors contribute to human memory processes remains unsettled.The occasional need to place depth electrodes within the mesial temporal lobes during the presurgical evaluation of patients with pharmacoresistant temporal lobe epilepsy affords us the opportunity to record depth potentials directly from the human hippocampal formation. Analyses of limbic event-related potentials (ERPs) can contribute to the presurgical workup with respect to both the lateralization of the epileptogenic focus (17-19) and the prediction of surgical outcome (20,21). Limbic ERPs also offer unique opportunities for investigating the relationship between hippocampal structures ...

Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia

“…Ketamine produces significant amplitude reductions in one of the most important sources of the N400, the antero-medial temporal lobe (AMTL) generator (Grunwald et al 1999). Thus, the N400 findings are consistent with P&S's notion of an NMDA-dependent relationship between cognitive disorganization in schizophrenia and contextual coordination.…”

“…Thus, the N400 findings are consistent with P&S's notion of an NMDA-dependent relationship between cognitive disorganization in schizophrenia and contextual coordination. However, ketamine does not alter the AMTL generator of the P600 (Grunwald et al 1999). Thus, context functions related to the inhibition of mental representations (i.e., N400) are impaired in schizophrenia, and associated with ketamine-induced MNDA/glutamate system damage.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Since then a number of NMDA receptor antagonists have been studied towards their ability to induce impairment of learning and memory. It is worth mentioning that similar findings have been found in human subjects, where by combining behavioural and electrophysiological data from patients with temporal lobe epilepsy exposed to ketamine, they demonstrated involvement of NMDA receptors in human memory processes (Grunwald et al, 1999).…”

How Progesterone Impairs Memory for Biologically Salient Stimuli in Healthy Young Women

“…Glutamate but not GABA turnover is crucial for memory by inducing longterm potentiation (LTP) via NMDA receptor activation (Morris et al, 1986). Indeed, NMDA receptor antagonists impair human memory by affecting medial temporal lobe memory processes (Grunwald et al, 1999). In contrast, allopregnanolone reduced the response amplitude to all stimuli, regardless of whether the item was memorized or retrieved successfully.…”