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.SIGNIFICANCE STATEMENT The G2019S mutation in LRRK2 causes late-onset Parkinson's disease (PD). LRRK2 is highly expressed in striatal neurons throughout life, but it is unclear how mutant LRRK2 affects striatal neuron function and behaviors in young adulthood. We addressed this question using Lrrk2-G2019S knock-in mice. The data show that young adult G2019S mice were unusually resilient to a depression-like syndrome resulting from chronic social stress. Further, mutant striatal synapses were incapable of forms of synaptic plasticity normally accompanying depression-like behavior and important for supporting the full range of cognitive function. These data suggest that in humans, LRRK2 mutation may affect striatal circuit function in ways that alter normal responses to stress and could be relevant for treatment strategies for non-motor PD symptoms.
Keywords: LRRK2; LTP; chronic social defeat stress; nucleus accumbens; resilience; striatum.
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