Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

Background α-Synuclein misfolding and aggregation contribute to synaptic dysfunction in synucleinopathies, including Parkinson’s disease. However, the mechanism underlying the effect of α-synuclein on synaptic components remains unclear. Since the N-methyl-D-aspartic acid receptor (NMDAR) plays a key role in glutamate synapse pathophysiology, we here investigated its surface dynamics and functional distribution in neurons exposed to various pathological α-synuclein forms. Methods A combination of single-molecule tracking, immunochemistry, immunoblot and calcium imaging approaches were used to assess the changes in NMDAR membrane dynamics and functions. The NMDAR alterations were evaluated in rat cultured hippocampal networks, in which α-synuclein mutants were overexpressed or exposed to α-synuclein proteins (monomeric/PFF α-synuclein). The surface dynamics of NMDAR subtype was artificially tuned in order to test its instrumental role. Results We observed that mutant α-synuclein (A53T-α-synuclein) restricted NMDAR surface trafficking and impaired synaptic function. In contrast, wild-type α-synuclein did not affect synaptic NMDAR. Further, we found that chronic exposure to α-synuclein preformed fibrils induced molecular dysfunctions that mainly targeted the GluN2B-NMDAR subtype. The deficits of synaptic NMDAR have also been found in A53T transgenic mice α-synuclein. Upon fine-tuning of the surface dynamics of GluN2B-NMDAR, pathological α-synuclein gradually lost its synaptic toxicity. Conclusions Our findings indicate that pathological α-synuclein alters GluN2B-NMDAR synaptic dynamics and organization, which leads to glutamate synapse dysfunction.

Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis

Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)–mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.