BDNF rescues absence seizures and their comorbid memory deficits

Morais, Tatiana 2022. BDNF rescues absence seizures and their comorbid memory deficits. PhD Thesis, Cardiff University. Item availability restricted.

	PDF (PhD Thesis) - Accepted Post-Print Version Restricted to Repository staff only until 16 March 2025 due to copyright restrictions. Download (6MB)
	PDF (Publication form) - Supplemental Material Restricted to Repository staff only Download (391kB)

Abstract

Absence Seizures (ASs) are genetic generalized seizures consisting of sudden and relatively brief lapses of consciousness that are invariably accompanied by spike-and-wave discharges in the EEG. Notwithstanding the general view of ASs being relatively benign, recent studies in Childhood Absence Epilepsy cohorts (where ASs are the only seizure type) have now conclusively shown that 30% of these children are pharmaco-resistant and 60% show neuropsychiatric comorbidities that may precede the epilepsy diagnosis and can persist even after full pharmacological control of the seizures. Studies in various genetic and pharmacological models of ASs has demonstrated that a constitutively enhanced tonic GABAA inhibition in thalamic neurons is necessary and sufficient for the expression of ASs. On the basis of indirect evidence, this abnormality was suggested to result from a loss-of-function of the GABA transporter GAT1. Notably, medicines that supposedly increase GABA levels (e.g. tiagabine, vigabatrin) induce or aggravates ASs in humans and magnetic resonance spectroscopy showed higher GABA levels in an child with unilateral spike-and-wave discharges. In this thesis, I investigated directly the GAT1 function by measuring GABA uptake in different brain regions that are key for the expression of ASs and their comorbid memory deficits in two AS models, the Genetic Absence Epilepsy Rat from Strasbourg(GAERS) and the Stargazer (STG) mice. I also investigated the extent of the memory deficits in GAERS using different working and recognition memory tests. Moreover, since Brain Derived Neurotrophic Factor (BDNF) has been shown to increase GAT1 activity in normal animals, I investigated the effect of exogenous administration of this neurotrophin on ASs and memory impairments in freely moving GAERS rats. My results show that GAERS rats and STG mice have a smaller GAT1-mediated GABA uptake (compared to their respective non-epileptic control animals) in brain regions important for ASs (i.e., the thalamus and the somatosensory cortex) and their comorbid memory deficits (i.e. motor cortex, visual cortex and hippocampus), with no difference in GAT3-mediated GABA uptake. Moreover, in GAERS rats BDNF rescues the deficient GAT1-mediated GABA uptake in vitro and ASs and their comorbid memory deficits in vivo. Thus, my work highlights for the first time the existence of a common molecular and cellular pathway that controls both ASs and their comorbid memory deficits.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	7 March 2022
Date of Acceptance:	7 March 2022
Last Modified:	02 Apr 2024 10:18
URI:	https://orca.cardiff.ac.uk/id/eprint/148058

Actions (repository staff only)

Edit Item