title: Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2), which are associated with autosomal dominant Parkinson's disease, elicit progressive dendrite degeneration in neurons. We hypothesized that synaptic dysregulation contributes to mutant LRRK2-induced dendritic injury. We performed in vitro whole-cell voltage clamp studies of glutamatergic receptor agonist responses and glutamatergic synaptic activity in cultured rat cortical neurons expressing full-length wild-type and mutant forms of LRRK2. Expression of the pathogenic G2019S or R1441C LRRK2 mutants resulted in larger whole-cell current responses to direct application of AMPA and NMDA receptor agonists. In addition, mutant LRRK2-expressing neurons exhibited an increased frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in conjunction with increased excitatory synapse density as assessed by immunofluorescence for PSD95 and VGLUT1. Mutant LRRK2-expressing neurons showed enhanced vulnerability to acute synaptic glutamate stress. Furthermore, treatment with the NMDA receptor antagonist memantine significantly protected against subsequent losses in dendrite length and branching complexity. These data demonstrate an early association between mutant LRRK2 and increased excitatory synapse activity, implicating an excitotoxic contribution to mutant LRRK2 induced dendrite degeneration.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Plowey
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; The Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Steer
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Eisenberg
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Valentino
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA; The Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: ctc4@pitt.edu.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D005971:Glutamates / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008559:Memantine / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000502:physiology
chemical_list: D015259:Dopamine Agents; D005971:Glutamates; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D002118:Calcium; D008559:Memantine
keywords: Calcium; Excitotoxicity; LRRK2; Neurodegeneration; Parkinson's Disease