Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy.
The mediodorsal (MD) and paraventricular (PV) thalamic nuclei play a significant role in limbic epilepsy, and previous reports have shown changes in GABA-A receptor (GABAAR) mediated synaptic function. In this study, we examined changes in the pharmacology of GABAergic drugs and the expression of the GABAAR subunits in the MD and PV neurons in epilepsy. We observed nucleus specific changes in the sensitivity of sIPSCs to zolpidem and phenobarbital in MD and PV neurons from epileptic animals. In contrast, the magnitude of change in electrically evoked response (eIPSC) to zolpidem and phenobarbital were uniformly diminished in both MD and PV neurons in epilepsy. Immunohistochemical studies revealed that in epilepsy, there was a reduction in GAD65 expression and NeuN positive neurons in the MD neurons. Also, there was a decrease in immunoreactivity of the alpha1 and beta2/3 subunit of GABAARs, but not the gamma2 of the GABAAR in both MD and PV in epilepsy. These findings demonstrate significant alterations in the pharmacology of GABA and GABAARs in a key region for seizure generation, which may have implications for the physiology and pharmacology of limbic epilepsy.
Rajasekaran
Karthik
K
Department of Neurology, University of Virginia, Health Sciences Center, Charlottesville, VA 22908, USA.
Sun
Chengsan
C
Bertram
Edward H
EH
D000818:Animals; D004827:Epilepsy / Q000378:metabolism*; D018682:GABA Agents / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D020645:Mediodorsal Thalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D020644:Midline Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D000077334:Zolpidem
D018682:GABA Agents; C546242:Gabra1 protein, rat; C502185:Gabrb2 protein, rat; C546276:Gabrb3 protein, rat; C546281:Gabrg2 protein, rat; D009419:Nerve Tissue Proteins; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D010634:Phenobarbital