Paraquat inhibits postsynaptic AMPA receptors on dopaminergic neurons in the substantia nigra pars compacta.
Parkinson's disease (PD) is a neurodegenerative disease that mainly affects dopaminergic (DA-ergic) neurons in the substantia nigra pars compacta (SNc). Glutamate modulates neuronal excitability, and a high concentration of glutamatergic receptors is found on DA-ergic neurons in the SNc. Paraquat (PQ) is a putative causative agent for PD. Its effects on synaptic glutamate transmission in SNc DA-ergic neurons were evaluated using whole-cell voltage-clamp recording in brain slices from 7- to 14-day-old Wistar rats. In the presence of bicuculline (BIC), strychnine, and dl-aminophosphonovaleric acid, PQ reversibly suppressed AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) in a concentration-dependent manner (P<0.05). In the presence of tetrodotoxin (1 microM), PQ (50 microM) significantly reduced the amplitudes, but not the frequencies, of miniature EPSCs in the SNc, suggesting PQ inhibited eEPSCs through a postsynaptic mechanism. Exogenous application of AMPA to induce AMPA-mediated inward currents excluded involvement of a presynaptic response. The AMPA-induced currents in the SNc were significantly reduced by PQ (50 microM) to 74% of control levels (P<0.05), supporting that PQ acts on postsynaptic AMPA receptors. No effect of PQ on eEPSCs was seen in the LD thalamic nucleus and hippocampus, showing PQ specifically inhibited DA-ergic neurons in the SNc. Our results demonstrate a novel mechanism of action of PQ on glutamate-gated postsynaptic AMPA receptors in SNc DA-ergic neurons. This effect may attenuate the excitability and function of DA-ergic neurons in the SNc, which may contribute to the pathogenesis of PD.
Lee
Chun-Yao
CY
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lee
Chien-Hsing
CH
Shih
Chien-Cheng
CC
Liou
Horng-Huei
HH