Altered expression of  3-containing GABAA receptors in the neocortex of patients with focal epilepsy

Abstract

Impaired transmission in GABAergic circuits is thought to contribute to the pathogenesis of epilepsy. Although it is well established that major reorganization of GABA(A) receptor subtypes occurs in the hippocampus of patients with medically refractory temporal lobe epilepsy (TLE), it is unclear whether this disorder is also associated with alterations in GABA(A) receptor subtypes in the neocortex. Here we have investigated immunohistochemically the subunit composition and neocortical distribution of three major GABA(A) receptor subtypes using antibodies specifically recognizing the subunits alpha1, alpha2, alpha3, beta2/3 and gamma2. Cortical tissue was obtained at surgery from patients with TLE and hippocampal sclerosis (HS; n = 9), TLE associated with neocortical lesions (non-HS; n = 12) and frontal lobe epilepsy (FLE; n = 5), with post-mortem samples serving as controls (n = 4). A distinct laminar and neuronal expression pattern of the alpha-subunit variants was found across the neocortical regions examined in the temporal and frontal lobes in both control and patient tissue samples. In the five patients with FLE, GABA(A) receptor subunit staining was unchanged as compared to controls. In patients with TLE we observed a marked decrease in alpha3-subunit staining in the superficial neocortical layers (I-III), but no change in the deep layers (V and VI) or in the expression pattern of the alpha1 and alpha2-subunits. Reduced expression in alpha3-containing GABA(A) receptors was detected in six out of nine patients of the HS group and four out of twelve patients of the non-HS group. Histopathological changes were present in eight out of the ten patients with decreased alpha3-subunit staining. The selective reduction in alpha3-containing GABA(A) receptors was confirmed using semiquantitative measurements of optical density (OD). The specific changes unique to alpha3-subunit expression in the superficial neocortical layers of patients with TLE suggest that this subtype is of particular significance in the reorganization of cortical GABAergic systems in focal epilepsy.

Longitudinal and cross-sectional analysis of atrophy in pharmacoresistant temporal lobe epilepsy

“…3 This may result in neuronal death and plasticity in both seizure-generating regions, and in neocortical circuits affected by seizure spread. 28 Thus, it is plausible that changes observed in the current study may be related to the combined effects of neuronal disconnection and seizure-related damage. However, the putative effects of genetic factors and antiepileptic drugs on atrophy progression cannot be ruled out.…”

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

“…The common theme emerging from the different reports strongly suggests that abnormalities in Reelin-mediated signaling not only increases the vulnerability to develop psychosis, it clearly promotes the development of moderate to severe cognitive dysfunctions. In addition to these psychiatric diseases, abnormalities in Reelin have been associated with some forms of human epilepsy, particularly mesial temporal lobe epilepsy (Haas et al, 2002) which is characterized by profound hippocampal sclerosis involving loss of pyramidal neurons, granule cell dispersion and reactive gliosis, as well as a significant reorganization of GABA A receptor subunit expression (Loup et al, 2006;Loup et al, 2009). …”

GABAergic Dysfunction in Autism and Epilepsy

“…The presence of the seizures and altered behaviour was attributed to the loss of tonic inhibition to prevent hyperexcitability in the developing nervous system (Stork et al, 2000). GABA A receptor dysfunction has been well www.intechopen.com documented the hippocampus and neocortex in human epilepsy (Loup et al, 2000(Loup et al, , 2006. Animal models of temporal lobe epilepsy (Pirker et al, 2003) and absence seizures (Li et al, 2006) suggest alterations in receptor subunit expression and receptor localization as potential mechanisms.…”