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Acquired alterations in thalamic T-type calcium channels in models of neuronal hyperexcitability.

【摘要】 The thalamus has been identified as a neural pacemaker of both normal and abnormal rhythms, with low-threshold, transient (T-type) Ca2+ channels participating in this activity. The focus of this thesis is on the molecular and physiological alterations in thalamic T-type Ca2+ channels arising from neuronal insults that result in the generation of abnormal brain rhythms. These studies were performed in two mouse models of central nervous system (CNS) disorders involving neuronal hyperexcitability: a chemically-induced model of temporal lobe epilepsy (TLE), and a model of chronic alcohol withdrawal following repeated intermittent exposures to ethanol. In particular, one T-type Ca2+ channel isoform, CaV3.2, was investigated for its role in producing a hyperexcitable population of neurons in a specific midline thalamic nucleus, the reuniens (RE). The RE has strong connections with both the hippocampus and medial pre-frontal cortex (mPFC), and plays a key role in both normal and abnormal activity within this circuitry. My research shows that CaV3.2 is upregulated at key time points following chemically-induced seizures that correspond to both epileptogenesis (a time before the appearance of an epileptic condition) and a chronic period of spontaneous recurrent seizures (SRS). CaV3.2, along with an additional isoform CaV3.3, is also upregulated during repeated, intermittent ethanol exposures, with the upregulation of Ca V3.3 appearing to be dependent on increased CaV3.2 expression. Additionally, in both models, these changes produce a functional upregulation of the overall T-type Ca2+ current, including longer decay kinetics and depolarizing shifts in the voltage-dependent properties, thus leading to a greater tendency for RE neurons to participate in burst activity. These results suggest that changes in RE burst activity are due to alterations in T-type Ca2+ channel properties that result from the increased expression of an inducible T-type isoform, CaV3.2. Furthermore, the measured changes in thalamic T-type Ca2+ channels corresponded to behavioral correlates in both models. In the mouse model of acquired epilepsy, a reduced tendency for RE neurons to participate in T-type channel-mediated bursts was seen during the seizure-free period of epileptogenesis. In contrast, thalamic T-type channel changes that promote increased neuronal bursting were observed during a time period the corresponded to the chronic phase of SRS. In the intermittent ethanol exposure model, the observed time sequence involving the progressive upregulation of T-type channel expression and function closely mirrored disruptions in the theta band (4--9Hz) as measured by surface electroencephalogram (EEG). Therefore, increases in burst activity may play a key role in pathological hyperexcitability within thalamo-hippocampal circuitry, which could lead to either mild behavioral impairments stemming from disruptions in brain rhythms, or seizures through the generation or propagation of ictal activity from limbic regions.

【作者】 Graef, John D.;

【作者单位】 Wake Forest University.;

【授予单位】Wake Forest University.;

【学科】Biology, Neurobiology.;Biology, Physiology.

【学位】Ph.D.

【年(卷),期】2010(),

【年度】2010

【页码】306 p.

【总页数】306

【原文格式】PDF

【正文语种】eng

【中图分类】;

【原文服务方】国家工程技术数字图书馆

【关键词】;

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