Childhood absence epilepsy is an idiopathic, generalized non-convulsive epilepsy with a multifactorial genetic aetiology. Molecular-genetic analyses of affected human families and experimental models, together with neurobiological investigations, have led to important breakthroughs in the identification of candidate genes and loci, and potential pathophysiological mechanisms for this type of epilepsy. Here, we review these results, and compare the human and experimental phenotypes that have been investigated. Continuing efforts and comparisons of this type will help us to elucidate the multigenetic traits and pathophysiology of this form of generalized epilepsy.

Childhood absence epilepsy: genes, channels, neurons and networks.

Pathophysiological mechanisms of genetic absence epilepsy in the rat

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. The ducky gene was mapped previously to distal mouse chromosome 9. High-resolution genetic and physical mapping has resulted in the identification of the Cacna2d2 gene encoding the 22 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were found to underlie the ducky phenotype in the original ducky (du) strain and in a newly identified strain (du 2J ). Both mutations are predicted to result in loss of the full-length 22 protein. Functional analysis shows that the 22 subunit increases the maximum conductance of the 1A/4 channel combination when coexpressed in vitro in Xenopus oocytes. The Ca 2 channel current in acutely dissociated du/du cerebellar Purkinje cells was reduced, with no change in singlechannel conductance. In contrast, no effect on Ca 2 channel current was seen in cerebellar granule cells, results consistent with the high level of expression of the Cacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian 2 mutation and complete the association of each of the major classes of voltage-dependent Ca 2 chan

https://www.jneurosci.org/content/jneuro/21/16/6095.full.pdf

Ducky Mouse Phenotype of Epilepsy and Ataxia Is Associated with Mutations in the Cacna2d2 Gene and Decreased Calcium Channel Current in Cerebellar Purkinje Cells

y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. It exerts an inhibitory action in all forebrain structures, and it may play a role in the physiopathogenesis of certain neurological conditions, including epilepsy. Impairment of GABA functions produces seizures, whereas enhancement results in an anticonvulsant effect. Accordingly, several anticonvulsant drugs, including some antiepileptic drugs (AEDs), act by enhancing the efficacy of GABAmediated mechanisms (1,2). Numerous steps in GABA synaptic function are relevant to epileptogenesis: (a) GABA synthesis; (b) GABA release; (c) GABA transport; and (d) activation of receptors, subtypes A and B. Therefore several potential targets exist for epilepsy medications that are related to GABA. GABAA receptors apparently are particularly important in epileptogenesis and therapeutics. Several reviews have described the molecular and functional aspects of GABAA receptors (3-6). In this article, we summarize recent observations, conclusions, and hypotheses regarding the possible role of GABA in epileptogenesis. Much of the information is based on presentations made at the International Symposium “Focus on Epilepsy 111: GABA and Epileptogenesis” held in Whistler, B.C., in May 1995. A list of the faculty that participated in this conference is included in the Notes section.

GABA and Epileptogenesis

To understand the heterogeneity of gamma-aminobutyric acid type B receptor (GABABR)-mediated events, we investigated expression of GABABR1a and 1b mRNA variants in GABA and non-GABAergic neurons of the rat central nervous system (CNS), by using nonradioactive in situ hybridization histochemistry and, in combination with GABA immunocytochemistry, double labeling. In situ hybridization with a pan probe, which recognizes a common sequence of both GABABR1a and GABABR1b mRNA variants, demonstrated widespread expression of GABABR1 mRNA at various levels in the CNS. Both GABABR1a and GABABR1b were expressed in the neocortex, hippocampus, dorsal thalamus, habenula, and septum, but only GABABR1a was detected in cerebellar granule cells, in caudate putamen, and most hindbrain structures. A majority of GABA neurons in cerebral cortex showed hybridization signals for both GABABR1a and GABABR1b, whereas those in most subcortical structures expressed either or neither of the two. GABA neurons in thalamic reticular nucleus and caudate putamen hybridized primarily for GABABR1a. Purkinje cells in the cerebellar cortex expressed predominantly GABABR1b. GABA neurons in dorsal lateral geniculate nucleus did not display significant levels of either GABABR1a or GABABR1b mRNAs. These data suggested widespread availability of GABABR-mediated inhibition in the CNS. The differential but overlapping expression of GABABR1 mRNA variants in different neurons and brain structures may contribute to the heterogeneity of GABABR-mediated inhibition. Some GABA neurons possessed, but others might lack the molecular machinery for GABABR-mediated disinhibition, autoinhibition, or both.

Differential expression of γ‐aminobutyric acid type B receptor‐1a and ‐1b mRNA variants in GABA and non‐GABAergic neurons of the rat brain

In previous work we have shown that GABAB receptors are required for expression of absence seizures in the lethargic (lh/lh) mouse model; that lh/lh mice have increased numbers of GABAB binding sites compared to nonepileptic littermates (designated +/+); and that the magnitude of the increased number of GABAB receptors in lh/lh mice correlated positively with the frequency of absence seizures. We performed this study to delineate the neural network in which GABAB receptors regulate absence seizures in lh/lh mice. We designed three successive screens which had to be passed by a candidate neuronal population before it could be considered a member of the neural network in which GABAB receptors regulate absence seizures. First, the neuronal populations in lh/lh mice had to have enriched GABAB binding sites compared to homologous populations in matched nonepileptic controls; baclofen- displaceable 3H-GABA binding was measured in autoradiograms for this screen. Second, the candidate populations had to generate spike-wave discharges (SWDs) during absence seizures in lh/lh mice; bipolar recording electrodes implanted into candidate neuronal structures were used in this screen. Third, the candidate populations had to demonstrate GABAB receptor-mediated regulation of absence seizures in lh/lh mice; microinjections of a GABAB agonist [(-)-baclofen] and antagonist (CGP 35348) were used for this screen. In this study we found that anterior ventral lateral thalamic nucleus (VLa), nucleus reticularis thalami (NRT), nucleus reuniens (RE) passed all three screens, and hence are members of the neural network in which GABAB receptors regulate absence seizures in lh/lh mice.

https://www.jneurosci.org/content/jneuro/15/11/7367.full.pdf

Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model

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Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model