Age and associated hypertension impair hippocampal circuitry function and memory

Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140-200 Hz or the "ripple band") in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague-Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.