Excitatory ionotropic glutamate receptor expression in the reticular thalamic nucleus in a mouse model of absence epilepsy
Barad, Zsuzsanna
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Barad, Z. (2017). Excitatory ionotropic glutamate receptor expression in the reticular thalamic nucleus in a mouse model of absence epilepsy (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/7059
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http://hdl.handle.net/10523/7059
Abstract:
Absence epilepsy refers to a group of genetic, generalized epilepsy syndromes associated with absence seizures, which are especially common in children and juveniles. Childhood absence epilepsy (CAE) is the most prevalent childhood onset epilepsy, accounting for about 10-17% of all paediatric epilepsies. Absence seizures can occur up to hundreds of times a day in affected individuals, and are accompanied by behavioural arrest and loss of awareness. Secondary complications, such as accidental injury, and adverse psychiatric or behavioural comorbidities often appear in patients. Approximately one third of patients do not respond to available anti-epileptic medications. Thus, further research is required to decipher seizure mechanisms in order to identify additional molecular, or cellular targets for treatment.
The electroclinical signature of absence seizures is the characteristic ‘spike-and-wave discharges’ (SWDs) of 2.5-4 Hz on the electroencephalogram. SWDs are thought to arise from excessive synchronous oscillations in the thalamocortical-corticothalamic (TC-CT) circuit. The TC-CT circuit is composed of thalamic and cortical nuclei connected via intricate long-range projections. Imbalance in excitatory-inhibitory neurotransmission in the circuit can promote altered synchronicity between circuit constituents, ultimately leading to hypersynchronous oscillations. A key component of the circuit is the inhibitory reticular thalamic nucleus (RTN), which receives collaterals of the excitatory corticothalamic and thalamocortical projections. In return, the RTN sends extensive inhibitory projections to dorsal relay thalamic neurons, through which it significantly controls TC transmission to the cortex. Thus, anatomically and functionally intermediate between the cortical and thalamic nodes, the RTN can fundamentally determine the synchronicity of circuit oscillations.
Altered excitation of the inhibitory RTN neurons may underlie SWDs in a well-established absence epilepsy model, the stargazer mouse, as imbalances in RTN excitability further affect its inhibitory output to thalamic relay neurons, and potentially altering TC-CT transmission. This work aimed to investigate the protein expression of predominant excitatory neurotransmitter receptors, the AMPA- and NMDA-type ionotropic glutamate receptors, in the epileptic RTN in the quest to elucidate absence seizure mechanisms. Studies were conducted to evaluate receptor protein expression in the RTN tissue by means of Western blot and fluorescent immunohistochemistry. Specific excitatory synapses on RTN neurons were probed using biochemical methods and post-embedding immunogold cytochemistry in epileptic and control mice. Furthermore, developmental expression profiles were also examined with Western blot to distinguish changes in protein expression that precede the SWD onset in mice.
The findings confirmed that AMPAR protein expression is markedly reduced in the epileptic RTN and at specific synapses on RTN neurons, and that AMPAR expression is decreased in young mice prior to the start of SWDs. In contrast, the results showed that NMDAR expression is unchanged in stargazer mice, before and after seizures emerge. Taken altogether, the results suggest that deficient AMPAR expression contributes to seizure generation and propagation. The findings of this study help to better understand the cellular and molecular alterations underlying absence seizures, and to ultimately unravel seizure mechanisms. This will enable the design of future treatment strategies in order to resolve current medical complications, including refractory seizures and paradoxical seizure exacerbation.
Date:
2017
Advisor:
Grattan, David
Degree Name:
Doctor of Philosophy
Degree Discipline:
Anatomy
Publisher:
University of Otago
Keywords:
absence epilepsy; ionotropic glutamate receptors; reticular thalamic nucleus
Research Type:
Thesis
Languages:
English
Collections
- Anatomy [249]
- Thesis - Doctoral [3454]