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Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.

Due to the role of astrocytes and microglia in the pathophysiology of epilepsy and limited studies of antiseizure medication (ASM) effects on glial cells, we studied tiagabine (TGB) and zonisamide (ZNS) in an astrocyte-microglia co-culture model of inflammation. Different concentrations of ZNS (10, 20, 40, 100 µg/ml) or TGB (1, 10, 20, 50 µg/ml) were added to primary rat astrocytes co-cultures with 5–10% (M5, physiological conditions) or 30–40% (M30, pathological inflammatory conditions) microglia for 24 h, aiming to study glial viability, microglial activation, connexin 43 (Cx43) expression and gap-junctional coupling. ZNS led to the reduction of glial viability by only 100 µg/ml under physiological conditions. By contrast, TGB revealed toxic effects with a significant, concentration-dependent reduction of glial viability under physiological and pathological conditions. After the incubation of M30 co-cultures with 20 µg/ml TGB, the microglial activation was significantly decreased and resting microglia slightly increased, suggesting possible anti-inflammatory features of TGB under inflammatory conditions. Otherwise, ZNS caused no significant changes of microglial phenotypes. The gap-junctional coupling was significantly decreased after the incubation of M5 co-cultures with 20 and 50 µg/ml TGB, which can be related to its anti-epileptic activity under noninflammatory conditions. A significant decrease of Cx43 expression and cell–cell coupling was found after the incubation of M30 co-cultures with 10 µg/ml ZNS, suggesting additional anti-seizure effects of ZNS with the disruption of glial gap-junctional communication under inflammatory conditions. TGB and ZNS differentially regulated the glial properties. Developing novel ASMs targeting glial cells may have future potential as an “add-on” therapy to classical ASMs targeting neurons.

Parkinson’s disease (PD) is one of neurodegenerative diseases characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The development of a neuroprotective therapy is crucial for mitigating features and progression of PD. Since autophagy induction has recently emerged as a promising neuroprotective strategy, this study aimed to identify autophagy-inducing compounds and evaluate their neuroprotective activity. Among 3,200 compounds consisting of FDA-approved drugs or are under active development, 547 compounds targeting neurological diseases were filtered in, and three compounds (sertraline, tiagabine and bicifadine) were finally identified to exhibit the autophagy-inducing activity and also demonstrated the autophagy-dependent neuroprotective action by inhibiting the mammalian target of rapamycin (mTOR) in 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells. Furthermore, the analysis of neurochemical changes suggested that the ability of those compounds to restore the quantity of cellular neurotransmitters such as betaine, 5-hydroxyindoleacetic acid and kynurenine might be linked to their neuroprotective function. In conclusion, compounds like sertraline, tiagabine, and bicifadine that have the ability to induce autophagy and inhibit mTOR might be repurposed as PD treatment to protect the neuronal cells.

Neurophysiological recordings are dominated by arhythmical activity whose spectra can be characterised by power-law functions, and on this basis are often referred to as reflecting scale-free brain dynamics (1/fβ). Relatively little is known regarding the neural generators and temporal dynamics of this arhythmical behaviour compared to rhythmical behaviour. Here we used Irregularly Resampled AutoSpectral Analysis (IRASA) to quantify β, in both the high (5–100 Hz, βhf) and low frequency bands (0.1–2.5 Hz, βlf) in MEG/EEG/ECoG recordings and to separate arhythmical from rhythmical modes of activity, such as, alpha rhythms. In MEG/EEG/ECoG data, we demonstrate that oscillatory alpha power dynamically correlates over time with βhf and similarly, participants with higher rhythmical alpha power have higher βhf. In a series of pharmaco-MEG investigations using the GABA reuptake inhibitor tiagabine, the glutamatergic AMPA receptor antagonist perampanel, the NMDA receptor antagonist ketamine and the mixed partial serotonergic agonist LSD, a variety of effects on both βhf and βlf were observed. Additionally, strong modulations of βhf were seen in monkey ECoG data during general anaesthesia using propofol and ketamine. We develop and test a unifying model which can explain, the 1/f nature of electrophysiological spectra, their dynamic interaction with oscillatory rhythms as well as the sensitivity of 1/f activity to drug interventions by considering electrophysiological spectra as being generated by a collection of stochastically perturbed damped oscillators having a distribution of relaxation rates. •The slope of the power spectrum (1/fβ) in the high frequency band is correlated with alpha band power in MEG/EEG/ECoG.•Ketamine and LSD lower the value of β in the high frequency band whereas perampanel and tiagabine increase β.•We propose a model to explain these data based on oscillators in the alpha band having a distribution of relaxation rates.

The human gamma aminobutyric acid transporter subtype 1 (hGAT1) located in the nerve terminals is known to catalyze the neuronal function by the electrogenic reuptake of γ-aminobutyric acid (GABA) with the co-transport of Na+ and Cl− ions. In the past, there has been a major research drive focused on the dysfunction of hGAT1 in several neurological disorders. Thus, hGAT1 of the GABAergic system has been well established as an attractive target for such diseased conditions. Till date, there are various reports about stereo selectivity of –COOH group of tiagabine, a Food and Drug Administration (FDA)-approved hGAT1-selective antiepileptic drug. However, the effect of the stereochemistry of the protonated –NH group of tiagabine has never been scrutinized. Therefore, in this study, tiagabine has been used to explore the binding hypothesis of different enantiomers of tiagabine. In addition, the impact of axial and equatorial configuration of the–COOH group attached at the meta position of the piperidine ring of tiagabine enantiomers was also investigated. Further, the stability of the finally selected four hGAT1–tiagabine enantiomers namely entries 3, 4, 6, and 9 was evaluated through 100 ns molecular dynamics (MD) simulations for the selection of the best probable tiagabine enantiomer. The results indicate that the protonated –NH group in the R-conformation and the –COOH group of Tiagabine in the equatorial configuration of entry 4 provide maximum strength in terms of interaction within the hGAT1 binding pocket to prevent the change in hGAT1 conformational state, i.e., from open-to-out to open-to-in as compared to other selected tiagabine enantiomers 3, 6, and 9.

γ-Aminobutyric acid (GABA) transporter 1 (GAT1) 1 regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy 2 . Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine 3 , with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition 4 . The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins. Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.

INTRODUCTION We examined how abnormal prefrontal neurophysiology and changes in gamma‐aminobutyric acid‐ergic (GABAergic) neurotransmission contribute to behavioral impairments in disorders associated with frontotemporal lobar degeneration (FTLD). METHODS We recorded magnetoencephalography during an adaptive visuomotor task from 11 people with behavioral‐variant frontotemporal dementia, 11 with progressive supranuclear palsy, and 20 age‐matched controls. We used tiagabine, a gamma‐aminobutyric acid (GABA) re‐uptake inhibitor, as a pharmacological probe to assess the role of GABA during motor‐related beta power changes. RESULTS Task impairments were associated with diminished movement‐related beta power. Tiagabine facilitated partial recovery of behavioral impairments and neurophysiology, moderated by executive function, such that the greatest improvements were seen in those with higher cognitive scores. The right prefrontal cortex was revealed as a key site of drug interaction. DISCUSSION Behavioral and neurophysiological deficits can be mitigated by enhancement of GABAergic neurotransmission. Clinical trials are warranted to test for enduring clinical benefits from this restorative‐psychopharmacology strategy. Highlights Event‐related beta power changes during movement can be altered by the GABA reuptake inhibitor, tiagabine. In people with behavioral‐variant frontotemporal dementia and progressive supranuclear palsy, tiagabine enhanced beta modulation and concurrently improved task performance, dependent on baseline cognition, and diagnosis. The effects of the drug suggest a GABA‐dependent beta‐related mechanism that underlies adaptive motor control. Restoring selective deficits in neurotransmission is a potential means to improve behavioral symptoms in patients with dementia.

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene result in syndromic X-linked intellectual disability (XLID). In addition to intellectual disability, patients with CUL4B mutations exhibit epilepsy. To date, the mechanism underlying epilepsy associated with CUL4B mutation has not been elucidated. Here, we show that male mice with Cul4b deleted in the nervous system are more susceptible to both pentylenetetrazole (PTZ)- and kainic acid (KA)-induced epilepsy and exhibit spontaneous epilepsy without any chemical inducers. We identify the CRL4B complex as an E3 ubiquitin ligase that targets GABA transporter 1 (GAT1). CUL4B deletion in male mice results in GAT1 accumulation and increased GABA reuptake, leading to impaired GABA-mediated inhibitory synaptic transmission. Treating CUL4B-deficient mice with the GAT1 inhibitor tiagabine effectively reverses the increased susceptibility to chemical-induced epilepsy and attenuates spontaneous epilepsy without the use of chemical inducers. We further confirm the role of CUL4B in the regulation of GAT1 levels and GABA uptake in neurons and astrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from patients with CUL4B loss-of-function mutations. Our work reveals a novel mechanism underlying the pathogenesis of epilepsy and identifies a promising drug target for treating CUL4B mutation-associated epilepsy.

γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2–3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine. Zhu et al. report four cryogenic electron microscopy structures of γ-aminobutyric acid transporter 1 at 2.2–3.2 Å in inward-occluded or inward-open conformations, and elucidate the molecular basis for γ-aminobutyric acid recognition and mode of action of two inhibitors, nipecotic acid and tiagabine.

Background Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first‐line treatment. Direct head‐to‐head comparisons are lacking. Methods Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview‐based outcome measures, active‐control conditions (e.g. supportive psychotherapy), and intent‐to‐treat analysis were selected for analyses. Independent review, data ion, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow‐up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta‐analyses for medication versus control, medication pre‐/posttreatment, psychotherapy versus control, and psychotherapy pre‐/posttreatment. Results Effect sizes for trauma‐focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. Conclusions Study findings support use of TFPs over nontrauma‐focused psychotherapy or medication as first‐line interventions. Second‐line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment‐as‐usual conditions. Direct head‐to‐head trials of TFPs versus sertraline or venlafaxine are needed.