Large aspiny neurons are the only non-GABAergic neurons in the striatum. After transient cerebral ischemia, large aspiny neurons survive while medium spiny neurons die. Previous studies have shown that differential changes in the intrinsic membrane properties and excitatory synaptic transmission play a role in this selective vulnerability. However, the role of inhibitory synaptic transmission in this selective vulnerability is still unknown. Since inhibitory tone is very important in the control of neuronal excitability, the present study is aimed at examining if there are any changes in inhibitory synaptic transmission in striatal neurons after ischemia and the possible mechanisms. We also examined if facilitation of inhibitory synaptic transmission by muscimol could attenuate ischemic neuronal injury in the striatum after ischemia. Results from this study will improve the understanding of the mechanisms underlying selective neuronal injury after transient cerebral ischemia. We hope this study could contribute to the translational studies for the stroke patients after cardiac arrest. / Indiana University-Purdue University Indianapolis (IUPUI) / In the striatum, large aspiny (LA) interneurons survive transient cerebral ischemia while medium spiny (MS) neurons die. Excitotoxicity is believed to be the major cause for neuronal death after ischemia. Since inhibitory tone plays an important role in the control of neuronal excitability, the present study is aimed at examining if there are any changes in inhibitory synaptic transmission in striatal neurons after ischemia and the possible mechanisms.
Transient forebrain ischemia was induced in male Wistar rats using the four-vessel occlusion method. Inhibitory postsynaptic currents (IPSCs) were evoked intrastriatally and whole-cell voltage-clamp recording was performed on striatal slices. The expression of glutamate decarboxylase65 (GAD65) was analyzed using immunohistochemical studies and Western blotting. Muscimol (a specific GABAA receptor agonist) was injected intraperitoneally to the rats (1 mg/kg) to observe ischemic damage, evaluated by counting the survived cells in the striatum after hematoxylin & eosin (HE) staining.
The amplitudes of evoked IPSCs were significantly increased in LA neurons while depressed in MS neurons after ischemia. This enhancement was due to the increase of presynaptic release. Muscimol (1 μM) presynaptically facilitated inhibitory synaptic transmission in LA neurons at 24 h after ischemia. The optical density of GAD65-positive terminals and the number of GAD65-positive puncta was significantly increased in the striatum at both 1 day and 3 days after ischemia. Consistently, data from western blotting suggested an increased expression of GAD65 in the striatum after ischemia. For the rats treated with muscimol, the number of survived cells in the striatum was greatly increased compared to the non-treatment group.
The present study demonstrates an enhancement of inhibitory synaptic transmission in LA neurons after ischemia, which is contributed by two mechanisms. One is the increased presynaptic release of GABA mediated by presynaptic GABAA receptors. The other is the increased expression of GAD. Facilitation of inhibitory synaptic transmission by muscimol protects striatal neurons against ischemia. Therefore, the enhancement of inhibitory synaptic transmission might reduce excitotoxicity and contribute to the selective survival of LA neurons after ischemia.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/2021 |
| Date | 08 December 2009 |
| Creators | Li, Yan |
| Contributors | Xu, Zao C., Cummins, Theodore R., Yang, Charles R., Zhou, Feng C. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
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