GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Taylor, Stephan F.; Tso, Ivy F.

doi:10.1016/j.schres.2014.10.011

Cited by 104 publications

(76 citation statements)

References 106 publications

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“…Consistent with this possibility, pharmacological models of SCZ often propose a distributed disruption in E/I across cortical circuits. This finding is supported by clinical magnetic resonance spectroscopy studies showing GABA and glutamate deficits across the cortex in SCZ (7,(82)(83)(84).…”

Section: Focal Vs Global Neuropathology Producing Preferential Assocsupporting

confidence: 56%

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Yang

Murray

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

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Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined restingstate functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia.functional connectivity | schizophrenia | computational modeling S chizophrenia (SCZ) is a disabling psychiatric disease associated with widespread neural disturbances. These involve abnormal neurodevelopment (1-3), neurochemistry (4-7), neuronal gene expression (8-11), and altered microscale neural architecture (2). Such deficits are hypothesized to impact excitation-inhibition (E/I) balance in cortical microcircuits (12). Clinically, SCZ patients display a wide range of symptoms, including delusions, hallucinations (13, 14), higher-level cognitive deficits (15, 16), and lower-level sensory alterations (17). This display is consistent with a widespread neuropathology (18), such as the E/I imbalance suggested by the NMDA receptor (NMDAR) hypofunction model (19-21). However, emerging resting-state functional magnetic resonance imaging (rs-fMRI) studies implicate more networkspecific abnormalities in SCZ. Typically, these alterations are localized to higher-order association regions, such as the frontoparietal control network (FPCN) (18,22) and the default mode network (DMN) (23, 24), with corresponding disturbances in thalamo-cortical circuits connecting to association regions (25,26). It remains unknown how to reconcile widespread cellularlevel neuropathology in SCZ (20,21,27,28) with preferential association network disruptions (29,30).Currently a tension exists between two competing frameworks: global versus localized neural dysfunction in SCZ. Association network alterations in SCZ, identified via neuroimaging, may arise from a localized dysfunction (3,9,31,32). Alternatively, they may represent preferential abnormalities arising emergently from a nonspecific global microcircuit disruption (20, 33). Mechanistically, an emergent preferential effect could occur because of intrinsic differences between cortical ...

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Section: Focal Vs Global Neuropathology Producing Preferential Assocsupporting

confidence: 56%

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Yang

Murray

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

View full text Add to dashboard Cite

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“…2003, Gonzalez‐Burgos et al . 2010, Taylor & Tso 2014) as well as reduced capacity to generate gamma oscillations, as an important pathophysiological mechanism in schizophrenia (Uhlhaas & Singer 2010, Lewis et al . 2012).…”

Section: Discussionmentioning

confidence: 99%

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

et al. 2016

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AimTo date, the understanding and development of novel treatments for mental illness is hampered by inadequate animal models. For instance, it is unclear to what extent commonly used behavioural tests in animals can inform us on the mental and affective aspects of schizophrenia.MethodsTo link pathophysiological processes in an animal model to clinical findings, we have here utilized the recently developed Df(h15q13)/+ mouse model for detailed investigations of cortical neuronal engagement during pre‐attentive processing of auditory information from two back‐translational auditory paradigms. We also investigate if compromised putative fast‐spiking interneurone (FSI) function can be restored through pharmacological intervention using the Kv3.1 channel opener RE1. Chronic multi‐array electrodes in primary auditory cortex were used to record single cell firing from putative pyramidal and FSI in awake animals during processing of auditory sensory information.ResultsWe find a decreased amplitude in the response to auditory stimuli and reduced recruitment of neurones to fast steady‐state gamma oscillatory activity. These results resemble encephalography recordings in patients with schizophrenia. Furthermore, the probability of interneurones to fire with low interspike intervals during 80 Hz auditory stimulation was reduced in Df(h15q13)/+ mice, an effect that was partially reversed by the Kv3.1 channel modulator, RE1.ConclusionThis study offers insight into the consequences on a neuronal level of carrying the 15q13.3 microdeletion. Furthermore, it points to deficient functioning of interneurones as a potential pathophysiological mechanism in schizophrenia and suggests a therapeutic potential of Kv3.1 channel openers.

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“…59 The dysfunction of neurotransmitter GABA has been implicated in schizophrenia as well. 60 The GABA type B receptor 1 gene has been localized to 6p21.3, a region linked to schizophrenia. 61 An HERV-W long terminal repeat is present in the regulatory region of GABA type B receptor 1, which could potentially be involved in the altered expression of this gene.…”

Section: Pathological Liaisons Of Herv-wmentioning

confidence: 99%

Pathophysiological Role of HERV-W in Schizophrenia

Aftab¹,

Shah²,

Hashmi³

2016

JNP

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Schizophrenia is a neuropsychiatric disorder of complex etiology. Human endogenous retroviruses (HERVs) have been presented as possible candidates explaining the connections between the genetic, infectious, neurodevelopmental, and neuroinflammatory aspects of schizophrenia, with the human endogenous retrovirus type W family (HERV-W) showing the greatest evidence of association. Studies have identified retroviral nucleotide sequences, envelope and capsid proteins, and elevated transcription of HERV-W elements in CSF, blood, and brain samples from individuals with schizophrenia. The HERV-W elements can trigger the immune system in a variety of ways. HERV genetic elements may be activated by various prenatal maternal infections, leading to neuroinflammation and genetic abnormalities, altering the development of the brain, and eventually culminating in the development of schizophrenia. This review presents a concise synthesis of available evidence and theoretical speculation regarding the role of HERV-W in schizophrenia. The need for further investigation is highlighted before any conclusions can be stated with confidence.

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GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Cited by 104 publications

References 106 publications

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

Pathophysiological Role of HERV-W in Schizophrenia

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