Electrophysiological and molecular properties of calcium channels within basal forebrain neurons of Ca[subscript v]2.1 mutant tottering and leaner mice : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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College Station, Tex. :
Texas A&M University System Health Science Center,
2007.
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| Abstract: | ABSTRACT: The neuronal channelopathies are an expanding group of single gene disorders. Among these, voltage-gated calcium channels have been identified in numerous forms of epileptic and ataxic disorders. Several spontaneously occurring mouse mutants represent good models for human absence epilepsy, Episodic Ataxia Type-2, and Familial Hemiplegic Migraine mostnotably tottering (tg/tg) and leaner (tg [superscript la]/tg [superscript la) mice. These murine models harbor mutations in the gene encoding the pore-forming subunit [alpha subscript 1] of the Ca[subscript v]2.1 voltage-gated calcium ion channel and exhibit absence epilepsy, cerebellar degeneration, and ataxia. Ca[subscript v]2.1 calcium channels are widely expressed in the mammalian brain in a predominantly presynaptic distribution and have an important role in modulating neurotransmitter release. In cerebellar Purkinje cells where Ca[subscript v]2.1 channels are the primary calcium channel, the tottering and leaner mutations result in a significantly reduces whole-cell current. This is believed to be the impetus for the ataxia that is so pronounced in both the mouse models and the human diseases. But children suffering from absence epilepsy and ataxia also experience untreatable deficits that arise from brain regions where the calcium channel population is heterogeneous. One such area is the basal forebrain, where cholinergic and GABAergic cells play important roles in arousal, learning, and memory by modulating cortical and hippocampal activation. It remains unknown whether the diversity in the calcium channel population helps to alleviate or promote the observed clinical pathology. In this study, we used conventional patch-clamp electrophysiologic techniques and semi-quantitative reverse transcription PCR to investigate calcium channel plasticity in acutely dissociated basal forebrain neurons of tottering, leaner, compound heterozygote tottering/leaner, and wildtype C57BL/6J mice. We have shown that neurons from young tottering mice exhibited a significant increase in percentage of nifedipine-sensitive current (46.0%́±2.0; n=21) compared with young wildtype mice (27.8%±1.0; n=12; p,0.05). This increase is not due to an upregulation in either Ca[subscript v]1.2 or Ca[subscript v]1.3 transcription. Instead, there appears to be changes in the modulation of these calcium channels or in the channel function itself. Because, is some instances, the tottering mutant phenotype is reminiscent of the physiologic aging process, we have compared the electropohysiologic findings between young (average of 4 months) and aged (average of 26 months) tottering and wildtype cohorts. Consistent with the aging literature, HVA current density was indreased in aged wildtype mice (45.4±6.0pA/pF; n=16) compared to young wildtype (38.7±2.0pA/pF; n=98; p<0.05). This increase can be explained by a greater proportion of nifedipine-sensitive component in aged wildtype mice (40.6%±2.0, n+8; p<0.05). Increasingly, current densities from aged tottering neurons (45.6±8.6pA/pF, n=10) displayed equivalence with those from young tottering mice (47.0±2.8pA/pF; n=80). In both aged wildtype and young/aged tottering neurons, the altered whole-cell current appears to be mediated by an increase in the activity of nifedipine-sensitive channels. These data suggest that despite having diverse origins, aberrant calcium loads in the basal forebrain may induce confluent mechanisms that relay heavily on compensation provided by the Ca[subscript v]2.1 sub-family of channels and this neuronal plasticity has a physiologic ceiling. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of the Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2007." William H. Griffith III, Louise, C. Abbott, Gerald D. Frye, Alan R. Parrish, George E. Davis. |
| Physical Description: | xvi, 219 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 153-217). |