Abstracts

Rationale: Epidemiological studies reveal that the elderly have the highest incidence of seizure disorders. We are interested in mechanisms that increase the excitability of neurons in the aged brain and enhance its seizure susceptibility. Studies have reported that aging is associated with increased excitability of principal neurons. In area CA1 of the hippocampus it has been suggested that the enhanced excitability of pyramidal cells in aging may be associated with alterations in GABAergic inhibition stemming in part from a loss of O-LM interneurons in stratum oriens (SO). O-LM interneurons have cell bodies located in SO and axonal projections to stratum lacunosum moleculare. These interneurons are commonly associated with the neuropeptide somatostatin (SST) and participate in the modulation of inputs from extrahippocampal structures via the temporoammonic (TA) pathway. We hypothesize that the loss of these O-LM interneurons during aging will cause a loss of dendritic inhibition and a dysregulation of temporoammonic input to CA1 pyramidal cells. Methods: Fisher 344 Brown Norway F1 Hybrid rats, ages 3 (young) and 27-30 (old) months, were used for all experiments. The effect of aging on selected neuronal populations in area CA1 of the hippocampus was investigated using immunohistochemistry for the neuronal marker Neu-N as well as global (GAD-67) or subset-specific (parvalbumin and somatostatin (SST)) markers of GABAergic interneurons. Brain slice electrophysiology was used to examine changes in GABAergic inhibition of CA1 pyramidal cells. Finally, in vivo microdialysis was used to examine age-dependent changes in GABA release in the hippocampus. Results: In SO of area CA1 of aged rats a significant decrease in GAD-67 immunolabeling and a reduction in SST staining were evident. No changes were observed in other regions of CA1. These findings suggest a selective loss of O-LM interneurons in aging. To investigate the functional consequences of this loss of O-LM cells we compared GABAergic inhibition in brain slices from young and aged rats. In brain slices from 3 month old rats, stimulation of interneurons in SO or in stratum radiatum (SR) inhibited a subsequent excitatory postsynaptic potential (EPSP) evoked by stimulation of the TA pathway. In aged rats SR stimulation produced a similar inhibition of TA-evoked EPSPs. However, inhibition produced by SO stimulation was significantly reduced. These observations are consistent with a functional reduction in O-LM interneurons in aging. In vivo measurements of GABA release in CA1 revealed no basal differences in GABA efflux in young versus aged rats, but indicated a significant blunting in GABA efflux during high potassium/calcium infusion via reverse dialysis in aged rats. Conclusions: These findings suggest that in area CA1 of the hippocampus the age-dependent loss of interneurons in stratum oriens impairs dendritic inhibition of pyramidal cells. We suggest that this loss of dendritic inhibition dysregulates TA input to CA1, potentially contributing to the generation and spread of seizures. Supported by the Epilepsy Foundation.