Pacemaker channel function and regulation in the healthy and epileptic thalamus

Kuisle, Mira. Pacemaker channel function and regulation in the healthy and epileptic thalamus. 2007, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_7974

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The control of electrical activity in the brain is important for all brain-related behavior,
including attention, arousal, action, but also drowsiness and sleep. Voltage-gated ion channels
are central to all these aspects of neuronal excitability. Accordingly, malfunction of ion
channels, be it inherited or acquired, tremendously compromises brain function, and leads to
states of epilepsy, movement disorders, sensory deficits and neuropsychiatric disease.
Voltage-gated ion channels form a large class of pore-forming, transmembrane proteins,
and include channels selective for the major ions Na+, Ca2+, K+, Cl-, and HCO3
-. This family
also includes ion channels permeable for several ions. Amongst these, the hyperpolarizationactivated
cyclic nucleotide-gated cation-nonselective (HCN) channels occupy a unique
position. First, being hyperpolarization-, not depolarization-activated, these channels possess
the capacity to function as pacemakers. Second, in addition to the voltage-gating, HCN
channels are directly modulated by intracellular cAMP levels. Third, the channels show the
greatest sensitivity to brief periods of abnormal neuronal activity documented so far that
manifests as a change in expression and function after periods of hours to days following
abnormal electrical activity. This unique sensitivity has prompted an interest into how HCN
channels may underlie the transformation of well-balanced neuronal circuits into
hyperexcitable networks typically observed after an epileptic insult or after injury.
The wealth of novel information about the molecular and regulatory properties of HCN
channels accumulated over the past years raised a series of questions related to the function of
this unique ion channel in neuronal cells and networks, including those in the intact animal.
1. At the level of the neuronal network: How does abnormal HCN channel expression
and function causally relate to the emergence of pathological neuronal activity?
2. At the level of the neuron: Are there, and if yes, which are the cell-type specific modes
of cAMP-dependent regulation of the channels?
In my thesis, I have addressed these questions by combining electrophysiological,
imaging, and molecular biological techniques in healthy animals and a rat model of epilepsy.
1. We have used the GAERS model to investigate the properties of HCN channel
regulation in both pre-epileptic and chronically epileptic stages. This approach has allowed us
to address the temporal relation between abnormal HCN channel function and the emergence
of epilepsy. The findings imply that pacemaker currents undergo an abnormal regulation in
the cause of epileptogenesis, but remain unaffected in chronic epilepsy. Interestingly,
thalamic cells overcome these deficits by developing compensatory changes that stabilize
HCN channel function.
2. Neurotransmitter-mediated cAMP synthesis and subsequent enhancement of HCNcurrents
is a well-established mechanism that controls thalamic relay functions. The
maintenance of arousal and wakefulness is connected with tonic activity of the noradrenergic
locus coeruleus in the thalamocortical system. How and whether prolonged noradrenergic
input modulates HCN channels in thalamic nuclei is subject of the second part of my thesis.
Furthermore, a differential β-adrenergic subtype expression pattern in functionally distinct
thalamic nuclei suggests that there could be a nucleus-specific component in the control of
waking and sleep homeostasis. The results of my study indeed reveal a distinct β-adrenergic
regulation of HCN channels within the thalamus. A strong β-adrenergic regulation of HCNcurrents
appears to be pronounced in those portions being involved in sensory relay, while
they may not be associated with general arousal functions.
Advisors:Lüthi, Anita
Committee Members:Vogt, Kaspar and Rüegg, Markus A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology
UniBasel Contributors:Vogt, Kaspar and Rüegg, Markus A.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7974
Thesis status:Complete
Number of Pages:156
Identification Number:
edoc DOI:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 16:10

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