NMDA receptor remodeling and nNOS activation in mice after unilateral striatal injury with 6-OHDA

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective dopaminergic loss. Non dopaminergic neurotransmitters such as glutamate are also involved in PD progression. NMDA receptor/postsynaptic density protein 95 (PSD-95)/neuronal nitric oxide synthase (nNOS) activation is involved in neuronal excitability in PD. Here, we are focusing on the evaluating these post-synaptic protein levels in the 6-OHDA model of PD. Adult male C57BL/6 mice subjected to unilateral striatal injury with 6-OHDA were assessed at 1-, 2-, or 4-weeks post-lesion. Animals were subjected to an apomorphine-induced rotation test followed by the analysis of protein content, synaptic structure, and NOx production. All biochemical analysis was performed comparing the control versus lesioned sides of the same animal. 6-OHDA mice exhibited contralateral rotation activity, difficulties in coordinating movements, and changes in Iba-1 and glial fibrillary acidic protein (GFAP) expression during the whole period. At one week of survival, the mice showed a shift in NMDA composition, favoring the GluN2A subunit and increased PSD95 and nNOS expression and NOx formation. After two-weeks, a decrease in the total number of synapses was observed in the lesioned side. However, the number of excitatory synapses was increased with a higher content of GluN1 subunit and PSD95. After four weeks, NMDA receptor subunits restored to control levels. Interestingly, NOx formation in the serum increased. This study reveals, for the first time, the temporal course of behavioral deficits and glutamatergic synaptic plasticity through NMDAr subunit shift. Together, these data demonstrate that dopamine depletion leads to a fine adaptive response over time, which can be used for further studies of therapeutic management adjustments with the progression of PD.