GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Xu, Mengyi; Wong, Albert

doi:10.1038/aps.2017.172

Cited by 102 publications

(74 citation statements)

References 253 publications

(285 reference statements)

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“…The presence of IFN-γ receptors in both neurons and glia suggests that IFN-γ signaling can directly or indirectly influence the GABAergic neurotransmission. The altered GABAergic inhibition inevitably affects neurocircuits and contributes to cognitive dysfunctions in various neurological disorders (Contestabile et al, 2017;Xu and Wong, 2018). During the inflammatory processes triggered by aging, infection, injury or neurological disorders, specific immune cells (including T cells) that normally patrol in the compartments surrounding the brain parenchyma can infiltrate into the brain parenchyma and produce cytokines including IFN-γ (Filiano et al, 2017;Gemechu and Bentivoglio, 2012).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Flood

Korol

Ekselius

et al. 2019

Journal of Neuroimmunology

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A B S T R A C TThe neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-γ (IFN-γ) is a "pro-inflammatory" cytokine mainly produced by T lymphocytes, activates its corresponding receptor and plays important roles under both homeostatic and inflammatory conditions. However, the impact of IFN-γ on the γ-aminobutyric acid (GABA)-mediated currents in the hippocampus, a major brain region involved in the cognitive function, has not been investigated. Here we detected abundant expression of both IFN-γ receptor subunit gene transcripts (Ifngr1 and Ifngr2) in the rat hippocampus by quantitative PCR. In addition, we pre-incubated rat hippocampal slices with IFN-γ (100 ng/ml) and recorded GABA-activated spontaneous and miniature postsynaptic inhibitory currents (sIPSCs and mIPSCs) and tonic currents in hippocampal CA1 pyramidal neurons by the whole-cell patch-clamp method. The pre-incubation with IFN-γ increased the frequency but not the mean amplitude, rise time or decay time of both sIPSCs and mIPSCs in hippocampal CA1 pyramidal neurons, suggesting a presynaptic effect of IFN-γ. Moreover, the GABAactivated tonic currents were enhanced by IFN-γ. In conclusion, the potentiation of GABAergic currents in hippocampal neurons by IFN-γ may contribute to the disturbed neuronal excitability and cognitive dysfunction during neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Flood

Korol

Ekselius

et al. 2019

Journal of Neuroimmunology

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“…Indirect modulation of the glutamatergic system via positive allosteric modulators of AMPAR have shown nootropic properties in laboratory animals and human patients 96–100 . Direct modulation of glutamatergic pathway via antagonists, co-agonizing the glycine site, potentiatiating the activity of agonists via polyamines, neurosteroids, and histamines for purpose of cognitive enhancement has also been explored 101 .…”

Section: Discussionmentioning

confidence: 99%

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Lam

Chen

Xia

et al. 2020

Preprint

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BackgroundCognitive traits demonstrate significant genetic correlations with many psychiatric disorders and other health-related traits. Many neuropsychiatric and neurodegenerative disorders are marked by cognitive deficits. Therefore, genome-wide association studies (GWAS) of general cognitive ability might suggest potential targets for nootropic drug repurposing. Our previous effort to identify “druggable genes” (i.e., GWAS-identified genes that produce proteins targeted by known small molecules) was modestly powered due to the small cognitive GWAS sample available at the time. Since then, two large cognitive GWAS meta-analyses have reported 148 and 205 genome-wide significant loci, respectively. Additionally, large-scale gene expression databases, derived from post-mortem human brain, have recently been made available for GWAS annotation. Here, we 1) reconcile results from these two cognitive GWAS meta-analyses to further enhance power for locus discovery; 2) employ several complementary transcriptomic methods to identify genes in these loci with variants that are credibly associated with cognition; and 3) further annotate the resulting genes to identify “druggable” targets.MethodsGWAS summary statistics were harmonized and jointly analysed using Multi-Trait Analysis of GWAS [MTAG], which is optimized for handling sample overlaps. Downstream gene identification was carried out using MAGMA, S-PrediXcan/S-TissueXcan Transcriptomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via Summary-statistics Mendelian Randomization [SMR] and linkage methods [HEIDI], Available brain-specific eQTL databases included GTEXv7, BrainEAC, CommonMind, ROSMAP, and PsychENCODE. Intersecting credible genes were then annotated against multiple chemoinformatic databases [DGIdb, KI, and a published review on “druggability”].ResultsUsing our meta-analytic data set (N = 373,617) we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. 26 genes were associated with general cognitive ability via SMR, 16 genes via STissueXcan/S-PrediXcan, 47 genes via eQTL mapping, and 68 genes via MAGMA pathway analysis. The use of the HEIDI test permitted the exclusion of candidate genes that may have been artifactually associated to cognition due to linkage, rather than direct causal or indirect pleiotropic effects. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging on our various transcriptome and pathway analyses, as well as available chemoinformatic databases, we identified 16 putative genes that may suggest drug targets with nootropic properties.DiscussionResults converged on several categories of significant drug targets, including serotonergic and glutamatergic genes, voltage-gated ion channel genes, carbonic anhydrase genes, and phosphodiesterase genes. The current results represent the first efforts to apply a multi-method approach to integrate gene expression and SNP level data to identify credible actionable genes for general cognitive ability.

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“…Manipulating the GABAergic system provides another potential treatment target 46 . The GABAergic system shapes synchronized neuronal activity during oscillations [47][48][49][50][51] , and is impaired in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

In silico hippocampal modeling for multi-target pharmacotherapy in schizophrenia

2020

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Treatment of schizophrenia has had limited success in treating core cognitive symptoms. The evidence of multi-gene involvement suggests that multi-target therapy may be needed. Meanwhile, the complexity of schizophrenia pathophysiology and psychopathology, coupled with the species-specificity of much of the symptomatology, places limits on analysis via animal models, in vitro assays, and patient assessment. Multiscale computer modeling complements these traditional modes of study. Using a hippocampal CA3 computer model with 1200 neurons, we examined the effects of alterations in NMDAR, HCN (Ih current), and GABAAR on information flow (measured with normalized transfer entropy), and in gamma activity in local field potential (LFP). We found that altering NMDARs, GABAAR, Ih, individually or in combination, modified information flow in an inverted-U shape manner, with information flow reduced at low and high levels of these parameters. Theta-gamma phase-amplitude coupling also had an inverted-U shape relationship with NMDAR augmentation. The strong information flow was associated with an intermediate level of synchrony, seen as an intermediate level of gamma activity in the LFP, and an intermediate level of pyramidal cell excitability. Our results are consistent with the idea that overly low or high gamma power is associated with pathological information flow and information processing. These data suggest the need for careful titration of schizophrenia pharmacotherapy to avoid extremes that alter information flow in different ways. These results also identify gamma power as a potential biomarker for monitoring pathology and multi-target pharmacotherapy.

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GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Cited by 102 publications

References 253 publications

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

In silico hippocampal modeling for multi-target pharmacotherapy in schizophrenia

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