Brief ischemia causes long-term depression in midbrain dopamine neurons.
Degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) plays an important role in the pathophysiology of neurodegenerative diseases like Parkinsonism and vascular dementia. SNc dopamine neurons both in vitro and in vivo show sensitivity to hypoxic/ischemic conditions and undergo degeneration. In acute brain slices, these dopamine neurons undergo hyperpolarization during hypoxia and hypoglycemia, which results in silencing of the neurons. However, the role that SNc excitatory synapses play in this process is poorly understood. Here we examined the effect of oxygen/glucose deprivation (OGD) on glutamatergic synaptic transmission in the SNc in a rat midbrain slice preparation. OGD for 5 min caused pre-synaptic ischemic long-term depression (iLTD) of glutamate transmission, as both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and N-methyl-D-aspartate receptor-mediated synaptic currents in SNc dopamine neurons were depressed to a similar extent. This depression began immediately after exposure to OGD and was not recovered upon washout of OGD. Pharmacological studies revealed that the iLTD was triggered by a rise in post-synaptic intracellular calcium and mediated by activation of pre-synaptic adenosine A(1) receptors, which reduced glutamate-dependent synaptic transmission by activating ATP-dependent potassium channels. Furthermore, we observed that iLTD did not occlude tetanic long-term depression (LTD) at the SNc excitatory synapses, suggesting that these two forms of LTD involve different pathways. Taken together, our results showed that brief exposure to hypoxia and hypoglycemia results in LTD of synaptic activity at glutamatergic synapses onto SNc neurons and this phenomenon could represent a protective mechanism by reducing ischemia-induced excitotoxic injury to dopamine neurons.
Singh
Vineeta
V
Department of Neurology, University of California, San Francisco, Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Carman
Melissa
M
Roeper
Jochen
J
Bonci
Antonello
A
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D002470:Cell Survival / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D018698:Glutamic Acid / Q000502:physiology; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000502:physiology
D043682:Receptor, Adenosine A1; D018698:Glutamic Acid; D004298:Dopamine