Kamesh, A. | Search bioRxiv

bioRxiv2021

Surface GluA1 and glutamate transmission are increased in VPS35 D620N neurons and altered by LRRK2 kinase inhibition

Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A missense mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinsons disease. Here, we use a VPS35 D620N knock-in mouse to study the neurobiology of this mutation. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.

neuroscience↗

bioRxiv2020

Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5-PKC signaling

Bipolar disorder (BD) is characterized by cyclical alternations between mania and depression, often comorbid with psychosis, and suicide. The mood stabilizer lithium, compared to other medications, is the most efficient treatment for prevention of manic and depressive episodes. The pathophysiology of BD, and lithiums mode of action, are yet to be fully understood. Evidence suggests a change in the balance of excitatory/inhibitory activity, favouring excitation in BD. Here, we sought to establish a holistic appreciation of the neuronal consequences of lithium exposure in mouse cortical neurons and identify underlying mechanisms. We found that chronic (but not acute) lithium treatment significantly reduced intracellular calcium flux, specifically through the activation of the metabotropic glutamatergic receptor mGluR5. This was associated with altered phosphorylation of PKC and GSK3 kinases, reduced neuronal excitability, and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory/inhibitory balance in the network toward inhibition. Together, the results revealed how lithium dampens neuronal excitability and glutamatergic network activity, which are predicted to be overactive in the manic phase of BD. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium, but with reduced toxicity.

neuroscience↗