Onset of α5GABA-A Receptor Dependent Hippocampal Trisynaptic Circuit Dysfunction Is Associated Increased Age and Blood Pressure

Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to interrogate the functional integrity of the hippocampal trisynaptic circuit (HTC), which is known to participate in memory, to determine whether age-associated increases in MAP contributes to circuitry dysfunction that may lead to mild-cognitive impairment (MCR). Ripples, and specifically sharp-wave ripple oscillations, play a role in memory replay and consolidation during awake immobility among other behaviors. These synchronous high frequency local field potentials (LFPs) in the ripple band (140 to 200 Hz) serve as an HTC level surrogate marker for circuitry function in rodents, non-human primates, and humans. Thus, we asked whether age-associated increased MAP might alter ripple dynamics. Recognizing that each patient responds in a unique way to hypertension we used a within subject design wherein each animal served as its own control in the investigative model. We surgically implanted high density silicon probe electrodes in HTC CA1 of young and aged SD males to determine whether a nootropic drug, α5IA, a negative allosteric modulator of α5 subunit containing type-A GABA receptors, could detect aberrant modulation of ripples within each subject. Here we report that acute oral administration of α5IA selectively modulated ripple amplitude, but not its duration or frequency during epochs of awake immobility. The response of peak ripple amplitude to α5IA is substantially diminished when chronic MAP exceeds 160 mmHg, corresponding to significant hypertension. The results are consistent with a model in which age-associated increases in MAP is associated with dysfunctional α5 GABA-A receptor modulation of ripple amplitude, but not duration or frequency, as a potential precision biomarker for memory dysfunction.