Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory

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.

Figure 1. Histology.

Illustration of the smallest (dark grey) and largest (light grey) lesion observed bilaterally through the rostral and caudal extent of the HPC for each lesion group.

Figure 2. Post-operative seizure scores and HPC damage.

(A) Mean ± SEM seizure rating scores calculated for the 3 hr post-operative period, using equation (2). TTX significantly decreased NMDA mediated seizure activity (). (B) Mean ± SEM lesion extent calculated for each lesion group at the Recent and Remote intervals. All lesion groups sustained equivalent HPC damage.

Figure 3. Fear conditioning retention sessions.

Mean ± SEM (A) Recent time point. Percentage freezing during the context memory retention session for rats that underwent contextual fear conditioning 1 week prior to HPC surgery. Sham rats froze significantly more than either lesion group. (B) Remote time point. Percentage freezing during the context memory retention session for rats that underwent contextual fear conditioning 5 weeks prior to HPC surgery. Sham rats froze significantly more than either lesion group.