Parkinson’s disease-linked lrrk2-g2019s mutation alters synaptic plasticity and promotes resilience to chronic social stress in young adulthood

Abstract

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a prevalent cause of late-onset Parkinson’s disease, producing psychiatric and motor symptoms, including depression, that are indistinguishable from sporadic cases. Here we tested how this mutation impacts depression-related behaviors and associated synaptic responses and plasticity in mice expressing a Lrrk2-G2019S knock-in mutation. Young adult male G2019S knock-in and wild-type mice were subjected to chronic social defeat stress (CSDS), a validated depression model, and other tests of anhedonia, anxiety, and motor learning. We found that G2019S mice were highly resilient to CSDS, failing to exhibit social avoidance compared to wild-type mice, many of which exhibited prominent social avoidance and were thus susceptible to CSDS. In the absence of CSDS, no behavioral differences between genotypes were found. Whole-cell recordings of spiny projection neurons (SPNs) in the nucleus accumbens revealed that glutamatergic synapses in G2019S mice lacked functional calcium-permeable AMPARs, and following CSDS, failed to accumulate inwardly rectifying AMPAR responses characteristic of susceptible mice. Based on this abnormal AMPAR response profile, we asked whether long-term potentiation (LTP) of corticostriatal synaptic strength was affected. We found that both D1 receptor (D1R)-and D2R-SPNs in G2019S mutants were unable to express LTP, with D2R-SPNs abnormally expressing long-term depression following an LTP-induction protocol. Thus, G2019S promotes resilience to chronic social stress in young adulthood, likely reflecting synapses constrained in their ability to undergo experience-dependent plasticity. These unexpected findings may indicate early adaptive coping mechanisms imparted by the G2019S mutation.