Abstract
Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.
Highlights
In experiments designed to assess the role of the HPC in memory in rats, HPC damage produced by selective infusions of the neurotoxin N-methyl-D-aspartate (NMDA) have produced robust amnesia [1,2,3,4]
Consistent with other studies showing memory impairments following seizures, our current study suggests that seizure activity makes a modest contribution to retrograde amnesia following NMDA lesions
By manipulating the level of seizure activity produced by NMDA lesions, we have shown that the retrograde amnesia of rats in the high seizure versus low/no seizure groups is significant compared to the Sham control groups
Summary
In experiments designed to assess the role of the HPC in memory in rats, HPC damage produced by selective infusions of the neurotoxin N-methyl-D-aspartate (NMDA) have produced robust amnesia [1,2,3,4]. Though the damage produced by neurotoxic lesions has a high degree of selectivity, lesions of the HPC can cause less obvious disruption to distal network circuitry [5,6]. This has been a concern using neurotoxic lesions, as well as other permanent lesion techniques [7,8,9]. Because the seizure activity can be severe, it is important to determine the extent to which retrograde amnesia found after HPC lesions [1,11] is influenced by disruptive seizure activity propagating to non-HPC regions This seizure activity may not be as great a concern when using non-neurotoxic lesion techniques, leaving open the possibility that seizure activity could mediate differences in experimental results
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