Neurons in the neostriatum receive massive glutamatergic inputs from cerebral cortex and dopaminergic inputs from substantia nigra. Spiny neurons in the neostriatum are highly vulnerable to cerebral ischemia. Enhancement of glutamatergic excitatory synaptic transmissions has been implicated in ischemia-induced excitotoxic neuronal death. Dopamine concentration dramatically increases during ischemia. Despite enormous studies suggest that dopamine is involved in the ischemia-induced neuronal loss in the striatum, it remains unclear how dopamine interacts with glutamatergic excitotoxicity. The present study investigates the dopamine modulation on excitatory synaptic transmission in spiny neurons after ischemia. Transient forebrain ischemia was induced in male adult Wistar rats for ∼20 minutes using 4-VO model. Brain slices were prepared at different intervals after reperfusion. Whole-cell voltage-clamp recordings were performed on medium-sized neurons in the neostriatum to examine locally evoked excitatory postsynaptic currents (EPSCs) or spontaneous miniature EPSCs. Evoked EPSCs in spiny neurons were potentiated at 9 h after ischemia. The ischemia-induced potentiation in synaptic efficacy was associated with an enhancement of presynaptic release as demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and a decrease in the paired-pulse ratio. The amplitude of inward currents evoked by exogenous application of glutamate did not show significant changes after ischemia, suggesting that postsynaptic mechanism is not involved. The ischemia-induced increase in mEPSCs frequency was not affected by blockade of voltage-gated calcium channels, but it was eliminated in the absence of extracellular calcium. Bath application of ATP P2X receptor antagonist pyridoxal-phosphate-6- azophenyl-2',4'-disulfonic acid (PPADS) significantly reduced mEPSC frequency in ischemic neurons but had no effects on the control ones. Furthermore, the inhibitory effect of PPADS on ischemic neurons was abolished in Ca2+ -free external solution. We found that dopamine depressed EPSCs in post-ischemic neurons through D1-like receptors (D1Rs). D1Rs activation also reduced the frequency of miniature EPSCs and increased the paired-pulse ratio, suggesting a presynaptic mechanism. 8-Br-cAMP, an activator of cAMP-dependent protein kinase (PKA), mimicked the depressive effects of D1Rs activation. Bath application of Rp-cAMP, an inhibitor of PKA, blocked the D1Rs-induced depression of EPSCs in post-ischemic spiny neurons, although intracellularly applied Rp-cAMP had no effects. In addition, D1Rs failed to reduce EPSCs amplitude in the presence of adenosine A1 receptors (A1Rs) antagonist. These results indicate that excitatory synaptic transmissions in spiny neurons are potentiated after ischemia, which might be associated with excitotoxic cell death. However, dopamine, through D1Rs activation, depresses excitatory synaptic transmission in spiny neurons, suggesting that dopamine modulation on excitatory transmission does not contribute to the excitotoxicity after ischemia.
|Original language||English (US)|
|Journal||Journal of Cerebral Blood Flow and Metabolism|
|Issue number||SUPPL. 1|
|State||Published - Nov 13 2007|
ASJC Scopus subject areas
- Clinical Neurology
- Cardiology and Cardiovascular Medicine