GABAergic modulation of performance in response inhibition and interference control tasks

Background: Inhibitory control is a crucial executive function with high relevance to mental and physical well-being. However, there are still unanswered questions regarding its neural mechanisms, including the role of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Aims: This study examined the effects of lorazepam (0.5 mg and 1 mg), a positive allosteric modulator at the GABAA receptor, on response inhibition and interference control. We also explored the heterogeneity of inhibitory control and calculated delta plots to explore whether lorazepam affects the gradual build-up of inhibition and activation over time. Methods: N = 50 healthy participants performed antisaccade, Eriksen flanker and Simon tasks in a within-subjects, placebo-controlled, double-blind randomized design. Results: Lorazepam increased reaction time (RT) and error rates dose dependently in all tasks ( p ⩽ 0.005). In the antisaccade and Simon tasks, lorazepam increased congruency effects for error rate ( p ⩽ 0.029) but not RT ( p ⩾ 0.587). In the Eriksen flanker task, both congruency effects were increased by the drug ( p ⩽ 0.031). Delta plots did not reflect drug-induced changes in inhibition and activation over time. Delta plots for RT in the Simon task were negative-going, as expected, whereas those for the antisaccade and flanker tasks were positive-going. Conclusions: This study provides evidence for GABAergic involvement in performance on response inhibition and interference control tasks. Furthermore, our findings highlight the diversity of the broader construct of inhibitory control while also pointing out similarities between different inhibitory control tasks. In contrast to RT and error rates, the cognitive processes indexed by delta plots may not be sensitive to GABAergic modulation.

Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks

Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

Probing cortical excitability under GABAergic modulation

Cortical excitability, the variable response to a given cortical input, is widely studied in neuroscience, from slice experiments and in silico modeling work to human clinical settings. However, a unifying definition and a translational approach to the phenomenon are currently lacking. For example, at the onset of epileptic seizures, cortical excitability may impair resilience to perturbations (external or endogenous). In this study, we tested in vivo whether changes in cortical excitability quantified as evoked response to small perturbation corresponded to changes in resilience to larger perturbations. To do so, we used both cell-type circuit specific optogenetic stimulation in mice and direct intracranial stimulation in one human subject and quantified 1) evoked cortical responses to single pulses of varying intensity, and 2) evoked cortical facilitation and suppression to paired pulses at varying intervals. In the presence of a gamma-Aminobutyric acid (GABA) agonist or antagonist, we found that 1) cortical response to single pulses and 2) cortical facilitation decreased and increased, respectively. Additionally, using trains of opto-pulses in mice in the presence of a GABA agonist, we found increased resilience to the induction of seizures. With this study, we provide evidence for a tight correlation between cortical excitability and resilience, exploring a range of cortical dynamics, from physiological excitability, to pathological discharges. Our study carried out with two different stimulation methods in two species suggests that varying cortical excitability can be tracked with simple protocols involving minute short-lived perturbative stimuli.

Benefits and Challenges of Cannabis Use in the Treatment of Refractory Epilepsy

Introduction: Refractory epilepsy (RE) is a disease that causes continuous and debilitating seizures. Due to the ineffectiveness of antiepileptic therapies, there is a growing interest in drugs made with cannabidiol (CBD), a substance extracted from Cannabis. Objective: To point out benefits and challenges of the use of CBD in the treatment of RE. Methods: Literature review performed at PubMed, with the descriptors Epilepsy, Drug Therapy and Cannabis. Results: It is suggested that CBD is mediated by cannabinoid receptors coupled to protein G, by blockade of NMDA receptors, by GABAergic modulation, glutamatergic synapses and / or mechanisms involving noncannabinoid receptors. CBD can also oppose the actions of exogenous and endogenous cannabinoid agonists, due to the negative allosteric modulation. The benefits of CBD are: great therapeutic diversity, safety and tolerability, rare and mild side effects, low risk of drug interactions, and milder cognitive effects, when compared to other antiepileptic drugs. Despite the benefits, CBD has adverse effects such as drowsiness, appetite reduction, diarrhea, increased activity of liver enzymes and interaction with substances metabolized by cytochrome P450. Still, the inefficient regulation generates variation in the composition of the marketed drugs, which can lead to Δ9 - tetrahydrocannabinol (THC) intoxication. Conclusions: Thus, it is essential that the scientific community remains open to investigate the effects of CBD, given the advantages of its use for treating RE.

Neuroisualization of Pharmaco-EEG Effects of Leutragine by Normalized Cat Brain Electrograms

The central mechanisms of leutragine during inhalational administration were investigated by analyzing normalized brain cat electrograms obtained by the method of Fast Fourier Transform (FFT). According to the conducted pharmaco-electroencephalography (pharmaco-EEG) analysis, Leutragine demonstrates a maximum effect on the parameters of brain electrograms approximately 30 minutes after administration followed by its persistence for about 2 hours. The observed effect is characterized predominantly by a deprimation of all analyzed rhythms compared to the initial values. Normalized brain electrograms (NBE) are less pronounced in the area of the hippocampus, although being more pronounced in the area of the cingulate gyrus and posterior hypothalamus. This may indicate the leucinencephaline regulation of intracentral relations of the brain. The most significant effects obtained in high-frequency β- and γ-rhythms (about 20–25, 40 and 60 Hz) indicate an increase in the γ-activity of interneurons and inhibition of pyramidal cells, which may indicate an anti-anxiety, antidepressant, antiepileptic, analgesic and similar actions of the substance under study. The NBE parameters were found to identical under the action of Leutragine and the derivatives of gamma-aminobutyric acid (glutamine, gabapentin, pregabalin, and phenibut), mainly at frequencies of about 40 and 60 Hz. Similar NBE parameters were obtained under the action of nootropics (semax), which is expressed in the activation of the hippocampus and the hypothalamus posterior at frequencies of about 60–65 Hz. This suggests that the action of Leutragine reflects the mechanisms of GABAergic modulation of the hippocampus and prefrontal neocortex, at the same time as having a positive effect on mental performance, memory consolidation and cognitive function. Leutragine can be used to model and study mechanisms exhibiting a positive effect in the treatment of diseases caused, among other things, by the new coronavirus infection COVID-19.

Cadherin-13 is a critical regulator of GABAergic modulation in human stem cell derived neuronal networks

SummaryActivity in the healthy brain relies on concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders, however, obtaining mechanistic insight into these disruptions, with translational value for the human patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has strongly been associated to attention-deficit/hyperactivity disorder and comorbid disorders such as autism and schizophrenia. CDH13 localises at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and PV expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13-deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type specific contribution of disease genes to the E/I balance.