Increased GABAB receptor signaling in a rat model for schizophrenia

Selten, Martijn; Meyer, Francisca; Ba, Wang; Vallès, Astrid; Maas, Dorien A.; Negwer, Moritz; Eijsink, V.D.; Vugt, Ruben W. M. van; Hulten, Josephus A. van; Bakel, Nick H.M. van; Roosen, Joey; Linden, Robert J. van der; Schubert, Dirk W.; Verheij, Michel M.M.; Kasri, Nael Nadif; Martens, Gerard J.M.

doi:10.1038/srep34240

Cited by 15 publications

(18 citation statements)

References 74 publications

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“…Presynaptic GABA B receptors, in addition, can reduce calcium inflow and reduce neurotransmitter release 236 , 237 . A reduction of GABA B subunit expression has been observed in post-mortem studies of patients with schizophrenia 238 , 239 , patients with bipolar disorder 240 and patients with major depression 241 as well as animal models for schizophrenia 242 – 244 . However, more research is required to identify the exact role for GABA B receptors in psychiatric disorders.…”

Section: Changes To Synapses Formed By Pv Interneuronsmentioning

confidence: 99%

Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders

2018

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Neuronal networks consist of different types of neurons that all play their own role in order to maintain proper network function. The two main types of neurons segregate in excitatory and inhibitory neurons, which together regulate the flow of information through the network. It has been proposed that changes in the relative strength in these two opposing forces underlie the symptoms observed in psychiatric disorders, including autism and schizophrenia. Here, we review the role of alterations to the function of the inhibitory system as a cause of psychiatric disorders. First, we explore both patient and post-mortem evidence of inhibitory deficiency. We then discuss the function of different interneuron subtypes in the network and focus on the central role of a specific class of inhibitory neurons, parvalbumin-positive interneurons. Finally, we discuss genes known to be affected in different disorders and the effects that mutations in these genes have on the inhibitory system in cortex and hippocampus. We conclude that alterations to the inhibitory system are consistently identified in animal models of psychiatric disorders and, more specifically, that mutations affecting the function of parvalbumin-positive interneurons seem to play a central role in the symptoms observed in these disorders.

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Section: Changes To Synapses Formed By Pv Interneuronsmentioning

confidence: 99%

Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders

2018

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“…Inhibition of postsynaptic GABA B receptors can enhance LTP by lengthening NMDA receptor-mediated currents [145] . Inhibition of presynaptic GABA B receptor enhances GABA release, thereby decreasing calcium conductance and subsequent GABA release [146] .…”

Section: Gaba B Receptor Ligands As Cognitive Enhancersmentioning

confidence: 99%

“…Despite evidence for cognitive enhancing effects of GABA B receptor antagonists, few studies have examined these compounds in animal models of schizophrenia. For example, in a recent apomorphine-susceptible (APO-SUS) young rat model displaying schizophrenia-relevant features [146] , the level of GAD67 and the density of GAD67-positive cells were reduced. However, basal synaptic input to pyramidal neurons was unaltered.…”

Section: Gaba B Receptor Ligands As Cognitive Enhancersmentioning

confidence: 99%

“…Therefore, these findings are in line with the hypothesis that inhibition of presynaptic GABA B receptors could enhance GABA release. Decreased inhibitory drive from interneurons (eg, PV neurons) onto their postsynaptic targeted pyramidal neurons could be a core pathophysiological feature of schizophrenia [173] , and that reduced GABA neurotransmission is highly correlated to cognitive defects in schizophrenia [146] . GABA B receptor antagonists require further investigations, especially in animal models related to schizophrenia in order to determine their potential for treating cognitive impairments in schizophrenia.…”

Section: Gaba B Receptor Ligands As Cognitive Enhancersmentioning

confidence: 99%

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GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Wong

2018

Acta Pharmacol Sin

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Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing. Dysfunctional GABA interneuron activity can disrupt the excitatory/inhibitory (E/I) balance in the cortex, which could represent a core pathophysiological mechanism underlying cognitive dysfunction in schizophrenia. Recent research suggests that selective modulation of the GABAergic system is a promising intervention for the treatment of schizophrenia-associated cognitive defects. In this review, we summarized evidence from postmortem and animal studies for abnormal GABAergic neurotransmission in schizophrenia, and how altered GABA interneurons could disrupt neuronal oscillations. Next, we systemically reviewed a variety of up-to-date subtype-selective agonists, antagonists, positive and negative allosteric modulators (including dual allosteric modulators) for α5/α3/α2 GABA and GABA receptors, and summarized their pro-cognitive effects in animal behavioral tests and clinical trials. Finally, we also discuss various representative histone deacetylases (HDAC) inhibitors that target GABA system through epigenetic modulations, GABA prodrug and presynaptic GABA transporter inhibitors. This review provides important information on current potential GABA-associated therapies and future insights for development of more effective treatments.

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“…GABAergic interneurons play an important regulatory role in cortical microcircuits and encompass~20% of all myelinated axons in the neocortex 11,12 . The interneuron defect in SZ is characterized by a reduced PFC expression of GABA-related mRNAs, while the number and dendritic arborization of PFC interneurons is not affected [13][14][15] . In addition, in the PFC of SZ patients lower myelin levels are found 16 and postmortem SZ brain tissue shows reduced myelinand oligodendrocyte (OL)-related gene expression levels 17,18 .…”

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confidence: 99%

Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

et al. 2020

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Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits.

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Increased GABAB receptor signaling in a rat model for schizophrenia

Cited by 15 publications

References 74 publications

Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders

Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

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