LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress

Christopher A. Guevara, Bridget A. Matikainen-Ankney, Nebojsa Kezunovic, Katherine LeClair, Alexander P. Conway, Caroline Menard, Meghan E. Flanigan, Madeline Pfau, Scott J. Russo, Deanna L. Benson, George W. Huntley

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation LRRK2-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wild-type (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonia-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans. NEW & NOTEWORTHY Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset.

Original languageEnglish
Pages (from-to)2382-2389
Number of pages8
JournalJournal of Neurophysiology
Issue number6
StatePublished - Jun 2020


  • EPSCs
  • G2019S
  • Intrinsic excitability
  • Nucleus accumbens
  • Parkinson's disease
  • Social defeat stress


Dive into the research topics of 'LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress'. Together they form a unique fingerprint.

Cite this