Distinct roles of AdipoR1 and AdipoR2 in modulating neuronal firing homeostasis in response to adiponectin and AdipoRon

BACKGROUND: The regulation of neuronal network activity depends on interactions between intrinsic circuit mechanisms and metabolic signals. Adiponectin (APN) is a peripheral adipokine whose receptors are present in the central nervous system (CNS), but whether APN/APN receptor (AdipoR) signaling shapes network-level firing dynamics remains incompletely understood. METHODS: We used multi-electrode array (MEA) recordings in WT, APN-KO, AdipoR1-KO, and AdipoR2-KO primary cortical cultures to examine APN/AdipoR-associated regulation of network-level firing dynamics. Genetic and pharmacological experiments with native APN and the synthetic AdipoR agonist AdipoRon (AR) were complemented by dose-response, washout, time-matched control, developmental-control, ELISA, and bicuculline-challenge assays in neuronal cultures and human forebrain organoids. RESULTS: AR modulated WT network activity in a concentration-dependent manner, with strong suppression at higher concentrations and smaller or bidirectional effects at lower concentrations. APN was detectable in neuron-conditioned medium, supporting local APN-related signaling in the culture system. APN-KO and AdipoR1-KO cultures showed increased firing-rate-related activity relative to matched controls, whereas AdipoR2-KO cultures showed reduced basal firing. Native APN and AR produced distinct temporal profiles. In bicuculline-disinhibited networks, AR suppressed network firing, whereas APN did not acutely silence the networks in the same manner. CONCLUSION: These data support a role for AdipoR signaling in neuronal network balance and indicate non-identical contributions of AdipoR1 and AdipoR2 to firing-rate control, bursting, and synchrony. Collectively, these findings identify AdipoR1 and AdipoR2 as differential regulators of firing homeostasis and establish a metabolic pathway for the homeostatic control of neuronal network excitability.