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J Neurophysiol 81: 2066-2074, 1999;
0022-3077/99 $5.00
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The Journal of Neurophysiology Vol. 81 No. 5 May 1999, pp. 2066-2074
Copyright ©1999 by the American Physiological Society

Excitatory But Not Inhibitory Synaptic Transmission Is Reduced in Lethargic (Cacnb4lh) and Tottering (Cacna1atg) Mouse Thalami

Sarah J. Caddick,1 Chunsheng Wang,2 Colin F. Fletcher,4 Nancy A. Jenkins,4 Neal G. Copeland,4 and David A. Hosford2,3

 1Department of Neurology, Medical College of Virginia, Richmond, Virginia 23298;  2Department of Medicine, Division of Neurology and  3Department of Neurobiology, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North Carolina 27705; and  4Mammalian Genetics Laboratory, Advanced Biosciences Labs, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Caddick, Sarah J., Chunsheng Wang, Colin F. Fletcher, Nancy A. Jenkins, Neal G. Copeland, and David A. Hosford. Excitatory But Not Inhibitory Synaptic Transmission Is Reduced in Lethargic (Cacnb4lh) and Tottering (Cacna1atg) Mouse Thalami. J. Neurophysiol. 81: 2066-2074, 1999.Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4lh) and tottering (Cacna1atg) mouse thalami. Recent studies of the homozygous tottering (Cacna1atg) and lethargic mouse (Cacnb4lh) models of absence seizures have identified mutations in the genes encoding the alpha 1A and beta 4 subunits, respectively, of voltage-gated Ca2+ channels (VGCCs). beta  subunits normally regulate Ca2+ currents via a direct interaction with alpha 1 (pore-forming) subunits of VGCCs, and VGCCs are known to play a significant role in controlling the release of transmitter from presynaptic nerve terminals in the CNS. Because the gene mutation in Cacnb4lh homozygotes results in loss of the beta 4 subunit's binding site for alpha 1 subunits, we hypothesized that synaptic transmission would be altered in the CNS of Cacnb4lh homozygotes. We tested this hypothesis by using whole cell recordings of single cells in an in vitro slice preparation to investigate synaptic transmission in one of the critical neuronal populations that generate seizure activity in this strain, the somatosensory thalamus. The primary finding reported here is the observation of a significant decrease in glutamatergic synaptic transmission mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA receptors in somatosensory thalamic neurons of Cacnb4lh homozygotes compared with matched, nonepileptic mice. In contrast, there was no significant decrease in GABAergic transmission in Cacnb4lh homozygotes nor was there any difference in effects mediated by presynaptic GABAB receptors. We found a similar decrease in glutamatergic but not GABAergic responses in Cacna1atg homozygotes, suggesting that the independent mutations in the two strains each affected P/Q channel function by causing defective neurotransmitter release specific to glutamatergic synapses in the somatosensory thalamus. This may be an important factor underlying the generation of seizures in these models.




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