Sex-Specific Age-Related Changes in Excitatory and Inhibitory Intracortical Circuits in Mouse Primary Auditory Cortex

A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Presbycusis can be caused by a dysfunction of the peripheral and central auditory system, and these dysfunctions might differ between the sexes. To date, the circuit mechanisms in the central nervous system responsible for age-related auditory dysfunction remain mostly unknown. In the auditory cortex (ACtx), aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses, but which circuits are affected has been unclear. Here we investigated how auditory cortical microcircuits change with age and if sex-dependent differences existed. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch-clamp recordings from layer (L) 2/3 cells in the primary auditory cortex (A1) in young adult (2-3 months) and aged (older than 18 months) male and female CBA/CaJ mice which have normal peripheral hearing. We found that L2/3 cells in aged male animals display functional hypoconnectivity of inhibitory circuits originating from L2/3 and L4. Compared with cells from young adult mice, cells from aged male mice have weaker excitatory connections from L2/3. We also observed an increased diversity of excitatory and inhibitory inputs. These results suggest a sex-specific reduction and diversification in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.