TARGETING NMDA RECEPTORS THROUGH D-SERINE SUPPLEMENTATION IN A RAT MODEL OF PARKINSON’S DISEASE

Compelling evidence suggests that degeneration of nigrostriatal dopaminergic neurons leads to dysfunctional NMDA receptors in striatal neurons in Parkinson’s disease (PD) models, likely contributing to the loss of synaptic plasticity and the appearance of motor deficits.
D-serine is an endogenous co-agonist of NMDA receptors, acting at the glycine-binding site of the NR1 subunit. Recent studies have reported altered levels of D-serine in both animal models of PD and PD patients, at peripheral and central levels. However, it remains unclear whether these alterations play a causal role in disease progression or represent a consequence of neurodegeneration.
In the present study, we investigated the effects of D-serine supplementation on synaptic plasticity, neuronal survival, and motor behaviour in a rat model of PD based on viral vector-mediated overexpression of the human α-synuclein gene. D-serine was administered daily at 100 mg/kg i.p., either alone or in combination with L-DOPA, for 8 weeks, during which motor performance was assessed. Animals were then sacrificed for electrophysiological recordings and immunohistochemical analyses.
Our results show that, similarly to L-DOPA, D-serine preserved long-term potentiation (LTP), which was lost in vehicle-treated rats due to dopaminergic degeneration. This event may account for the observed partial recovery of motor deficits, particularly in the stepping test. D-serine did not exert neuroprotective effects, as assessed by immunohistochemical investigations. However, increased striatal dopamine levels were detected in D-serine-treated rats, particularly in combination with L-DOPA.
These findings support the potential use of D-serine as an add-on therapy to L-DOPA in PD.