Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia.
OBJECTIVE
Spiny neurons in the neostriatum are highly vulnerable to ischemia. Despite an enormous body of research suggesting that dopamine is involved in ischemia-induced neuronal loss in the striatum, it remains unclear how dopamine interacts with the glutamatergic excitotoxicity that is widely accepted as a major cause of ischemic cell death. Our study was designed to investigate the effects of dopamine D1 receptor (D1R) activation on excitatory neurotransmission in postischemic striatal neurons.


METHODS
We used the 4-vessel occlusion ischemia model and brain slice preparations. Whole-cell voltage-clamp recording was performed on striatal neurons to measure excitatory postsynaptic currents (EPSCs). Systemic administration of a D1R agonist after ischemia and hematoxylin/eosin staining were performed to evaluate the effects of D1R activation on ischemia-induced neuronal degeneration in the striatum.


RESULTS
D1R activation depressed EPSCs in postischemic striatal neurons. The depression was attributable to inhibition of presynaptic release. An activator of cAMP-dependent protein kinase A (PKA) mimicked the depressive effects of D1R activation. Bath application of a PKA inhibitor blocked the depression of EPSCs, whereas intracellular postsynaptic application of the PKA inhibitor had no effect. The D1R agonist failed to reduce EPSC amplitude in the presence of an adenosine A1 receptor antagonist. Systemic administration of a D1R agonist after ischemia significantly attenuated ischemia-induced cell death in the striatum.


CONCLUSIONS
These results indicate that D1R activation presynaptically depresses excitatory synaptic transmission in striatal neurons after ischemia through activation of PKA and adenosine A1 receptors and thus demonstrate a novel mechanism of D1R-mediated protection against ischemia.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, Indianapolis, IN 46202, USA.
Yuchun
Y
Zhang
Ping
P
Deng
Yiwen
Y
Ruan
Zao C
ZC
Xu
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008854:Microscopy, Electron; D017072:Neostriatum / Q000166:cytology / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009498:Neurotoxins / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D009498:Neurotoxins; D043682:Receptor, Adenosine A1; D017447:Receptors, Dopamine D1; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases