Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration

• Published in: Biochimica et biophysica acta 2014-09, Vol.1842 (9), p.1596-1603
• Main Authors: Plowey, Edward D., Johnson, Jon W., Steer, Erin, Zhu, Wan, Eisenberg, David A., Valentino, Natalie M., Liu, Yong-Jian, Chu, Charleen T.
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; Cells, Cultured; Dendrites - drug effects; Dendrites - physiology; Dopamine Agents - pharmacology; Electrophysiology; Excitotoxicity; Female; Glutamates - metabolism; Immunoenzyme Techniques; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2; Memantine - pharmacology; Mutation - genetics; Neurodegeneration; Neurons - drug effects; Neurons - physiology; Parkinson's Disease; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Synapses - drug effects; Synapses - physiology; Synaptosomes - physiology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.05.016

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. •Neurons expressing mutant LRRK2 exhibit increased glutamatergic excitability.•G2019S or R1441C, but not kinase dead, LRRK2 increases excitatory synapse density.•The NMDA receptor antagonist memantine reduces mutant LRRK2-induced dendrite retraction.•Altered calcium flux may function upstream of other known effects of mutant LRRK2.•Synaptic dysfunction represents an early feature of mutant LRRK2 toxicity.