GIRK CHANNELS SUPPORT SOCIAL MEMORY AND CA2 NETWORK ACTIVITY IN A MALE AND FEMALE MOUSE MODEL OF EARLY ALZHEIMER’S DISEASE-LIKE AMYLOIDOSIS

Although the hippocampal CA2 region plays a pivotal role in the ability to distinguish familiar from novel individuals (i.e., social memory), it remains poorly studied. This memory is impaired in early Alzheimer’s disease (AD), where soluble amyloid-β oligomers (oAβ) induce a state of hyperexcitability that underlies synaptic, network and cognitive alterations in other hippocampal regions such as CA1. Thus, we hypothesized that CA2 activity supports social memory under physiological conditions, and that normalizing neuronal excitability could restore oAβ-impaired social memory.
Here, using an early amyloidosis model induced by intracerebroventricular oAβ_1-42 injections in both sexes, we examined CA2 network activity by LFP recordings during social memory tests and analyzed neuronal activation and proteomic changes by immunohistochemistry and MALDI-TOF, respectively. We then evaluated the effects of normalizing excitability through selective pharmacological activation of neuronal GIRK channels, one of the key determinants of neuronal activity.
Our results revealed oAβ disrupted sociability and social memory in both sexes, as well as CA2 oscillatory activity and the protein profile assessed by MALDI-TOF. GIRK activation restored sociability, social memory and network dynamics, normalizing CA2 pyramidal neuron activation.
In conclusion, we identified sex differences in CA2 oscillatory dynamics underlying social memory, which are disrupted in early amyloidosis and restored through GIRK channel activation. This study improves our understanding of the neural basis of social memory in both health and disease, and support a role for GIRK channels as regulators of CA2 network function in early AD.
Acknowledgements: MCIN/AEI/10.13039/501100011033(PID2020-115823-GBI00;PID2024-155413NB-I00), JCCM/FEDER(SBPLY/21/180501/000150;SBPLY/24/180225/000181),UCLM/FEDER(2022-GRIN-34354;2025-GRIN-38530) to JDNL/LJD. ANDALUSIA ERDF(UPO-1380660), MCIN/AEI(PID2022-141997NB-I00) to RSC.