GABAergic Alterations in Neocortex of Patients with Pharmacoresistant Temporal Lobe Epilepsy Can Explain the Comorbidity of Anxiety and Depression: The Potential Impact of Clinical Factors

Abstract

Temporal lobe epilepsy (TLE) is a chronic neurodegenerative disease with a high prevalence of psychiatric disorders. Temporal neocortex contributes to either seizure propagation or generation in TLE, a situation that has been associated with alterations of the γ-amino-butyric acid (GABA) system. On the other hand, an impaired neurotransmission mediated by GABA in temporal neocortex has also been involved with the pathophysiology of psychiatric disorders. In spite of these situations, the role of the necortical GABA system in the comorbidity of TLE and mood disorders has not been investigated. The present study was designed to identify alterations in the GABA system such as binding to GABAA and GABAB receptors and benzodiazepine site, the tissue content of GABA and the expression of the mRNA encoding the α1–6, β1–3, and γ GABAA subunits, in the temporal neocortex of surgically treated patients with TLE with and without anxiety, and/or depression. Neocortex of patients with TLE and comorbid anxiety and/or depression showed increased expression of the mRNA encoding the γ2-subunit, reduced GABAB-induced G-protein activation in spite of elevated GABAB binding, and lower tissue content of GABA when compared to autopsy controls. Some of these changes significantly correlated with seizure frequency and duration of epilepsy. The results obtained suggest a dysfunction of the GABAergic neurotransmission in temporal neocortex of patients with TLE and comorbid anxiety and/or depression that could be also influenced by clinical factors such as seizure frequency and duration of illness.

Quantitative expression and localization of GABAB receptor protein subunits in hippocampi from patients with refractory temporal lobe epilepsy

“…The lower expression of both GABA B receptor subunits in TLE-HS compared to TLE-STG, could indicate a decline in GABA B receptors which would provide an explanation for the compromised GABA B functionality previously reported in pharmacological and electrophysiological studies in animal model and in human TLE (Billinton et al 2000;Princivalle et al 2002;Fürtinger et al 2003b;Mareš and Kubová 2015;Leung et al 2016;Rocha et al 2015). This may be affecting the formation of fully functional GABA B receptors: since the heterodimerisation of GABA B1 and GABA B2 in 1:1 stoichiometry is essential for receptor trafficking and G-protein activation, the GABA B2 subunit could be a potential target for the development of new agonists or activating transcription factors drugs, which may have a major clinical impact on the treatment of pharmaco-resistant TLE-HS patients.…”

“…Previous studies reported impaired GABA B receptor mediated currents in TLE (Straessle et al 2003;Rocha et al 2015). This study aimed to examine possible differences in GABA B1a, GABA B1b and GABA B2 mRNA and protein expression.…”

“…Unfortunately, neither PMC nor non-spiking TLE-STG is a perfect match for the TLE-HS samples of interest for the kind of experiments conducted here. However, there is no real alternative in human studies and it is not the first time that neocortex (STG) has been used in studies on TLE (Teichgrӓber et al 2009;Rocha et al 2015). Even human non-epileptogenic hippocampi removed for other reasons (such as temporal lobe tumours) cannot be considered an ideal control tissue for TLE-HS samples (Kovács et al 2012).…”

“…The strength of this approach includes the fact that both sample types contain the same DNA (reducing the risk of intersubjective variability caused by gene-gene or gene-environment interactions) and that both samples were obtained and processed in the same way. This approach also avoids the difficulties associated with comparing TLE-HS tissue removed during epilepsy surgery with PMC-HS tissue possibly affected by an agonal state and post-mortem changes (Preece et al 2003;Tomita 2004;Teichgrӓber et al, 2009;Rocha et al 2015).…”

Contribution of amygdala pathology to comorbid emotional disturbances in temporal lobe epilepsy

“…Depression accounts for 30% of these disorders, followed by anxiety (10-25%), psychosis (2-7%), and personality disorders falling under 2% (Gaitatzis et al, 2004). In addition, neuropsychiatric conditions such as bipolar disorder, ADHD, and sleep disorders are also observed (Kimiskidis et al, 2007;Kanner, 2011;Rocha et al, 2014). Female gender, high seizure frequency, and a symptomatic epilepsy syndrome were identified as risk factors for the development of anxiety and/or depression in epilepsy patients (Kimiskidis et al, 2007).…”