# Impact of human disease-causing mutation on striatal synaptic and behavioral plasticity

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $29,303

## Abstract

PROJECT SUMMARY
 The G2019S mutation is the most common of several mutations in leucine-rich repeat kinase 2
(LRRK2) causing up to 40% of familial Parkinson's disease in certain populations. This pathogenic point
mutation is autosomal dominant and increases kinase activity 2-3 fold. Disease progression in both motor and
non-motor symptoms of mutant LRRK2 carriers is similar to idiopathic cases suggesting common mechanisms,
but progress has been limited because LRRK2 biology is poorly understood and little is known of pathogenic
cellular or synaptic actions of G2019S-LRRK2.
 LRRK2 expression is high in spiny projection neurons (SPNs) of dorsal and ventral striatum, and rises
rapidly during axon ingrowth and excitatory synaptogenesis. The timing and location of expression suggests
that mutant LRRK2 may be maladaptively influencing development of excitatory circuits that impact striatal
function. To begin to test this idea, we probed glutamatergic synaptic function in SPNs in G2019S-LRRK2
knockin mice. We showed that early in postnatal life, G2019S-SPNs in dorsal striatum exhibit a significantly
abnormal increase in spontaneous excitatory synaptic currents (sEPSCs) compared to WT mice or mice
expressing a LRRK2 kinase-dead knockin mutation (D2017A). Such abnormal excitatory activity was observed
in both direct- and indirect-pathway SPNs, was normalized by LRRK2 kinase inhibitors, and was associated
with larger SPN dendritic spine-heads and sEPSC amplitudes.
 Dorsal striatal SPNs receive convergent input from cerebral cortex and control many types of goal-
directed behaviors, and the latter are thought to reflect balanced control of bidirectional changes in
corticostriatal synaptic strength. The early abnormalities in SPN synaptic function and structure suggest that
synaptic plasticity will be altered by G2019S-LRRK2 with consequences for striatally-based behaviors.
Preliminary data support both of these ideas. Together, we hypothesize that the normal balance between
mechanisms that strengthen or weaken synaptic transmission is altered in SPNs expressing G2019S-LRRK2
in a way that both reveals molecular signaling pathways targeted by mutant LRRK2 and that has predictable
consequences for behaviors. The proposed experiments will assess the impact of mutant LRRK2 on synapse
strengthening and weakening in subtype-identified SPNs; they will identify the molecular pathways and
mechanisms involved; they will determine if mutant LRRK2 alters behaviors associated with SPN synapse
plasticity; and they will test whether in vivo LRRK2 inhibition early in life ameliorates maladaptive effects on
synaptic and behavioral plasticity documented later in life.

## Key facts

- **NIH application ID:** 10054595
- **Project number:** 3R01NS107512-01A1S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Deanna L Benson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,303
- **Award type:** 3
- **Project period:** 2020-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054595

## Citation

> US National Institutes of Health, RePORTER application 10054595, Impact of human disease-causing mutation on striatal synaptic and behavioral plasticity (3R01NS107512-01A1S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10054595. Licensed CC0.

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