Inhibitory neurosteroid reverses the dendritic spine disorder caused by gain-of-function GABAAR epilepsy variants

GABAA receptors (GABAARs) are key orchestrators of neuronal activity and several GABAAR variants have been linked to genetic neurodevelopmental disorders (NDDs) and epilepsies. Here, we report two variants (Met263Lys, Leu267Ile) in the predominant GABAAR α1 subunit gene (GABRA1) that increase apparent receptor affinity for GABA and confer spontaneous receptor activity. These gain-of-function features are unusual because GABAAR variants are traditionally thought to cause seizures by reducing inhibitory neurotransmission. Both Met263Lys and Leu267Ile increased tonic and spontaneous GABAergic conductances in neurons revealed by competitive inhibition and channel block of GABAARs. Significantly, α1-subunit variant expression in hippocampal neurons also reduced dendritic spine density. Our results indicate that elevated GABAergic signalling can precipitate genetic epilepsies and NDDs. Furthermore, the mechanistic basis may involve the de-compartmentalisation of excitatory inputs due to the removal of dendritic spines. This aberrant structural plasticity can be reversed by the naturally-occurring, therapeutically-tractable, inhibitory neurosteroid, pregnenolone sulphate.

Drug-resistant epilepsy: modern concepts, integrative mechanisms, and therapeutic advances

Background: Drug-resistant epilepsy is the cause of severe disability. Multiple questions remain unanswered both in terms of pathogenesis and therapeutic management. For this narrative review, PubMed database and Infomedica library were searched by using “drug-resistance in epilepsy” and “treatment of drug-resistant epilepsy” as key words. The following filters were applied: “Clinical Trial”, “Meta-analysis”, “Multicenter Study”, and “Randomized Controlled Trial”, covering the period of 01.01.2005–06.01.2021.Several hypotheses have been proposed, i.e., pharmacokinetic, intrinsic severity, gene, target, transporter, and neural network hypotheses. Many controlled trials showed different results in terms of seizure control after combined methods of therapies. Immunotherapy, palliative epilepsy surgery alone or associated with neurostimulation procedures including vagus nerve, trigeminal nerve, or deep brain stimulation may be efficient, however, seizure freedom is not always achieved. Genetic epilepsies might benefit from gene and exosome therapy; however, further studies are needed to verify their safety. Conclusions: Neuroscience of drug-resistant epilepsy faces many challenges. Inflammatory mediators, biomarkers, and genes might allow the identification of new treatment targets, contribute to an earlier diagnosis, and assess the clinical outcomes

Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies

A monogenic aetiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities and treatment choices. In this narrative review, we summarise concepts on the genetic epilepsies based on the underlying pathophysiological mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic aetiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification and functional characterization of specific somatic mutations before surgery using cerebrospinal fluid liquid biopsy or after surgery in brain specimens, will likely be integrated in planning surgical strategies and re-intervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.