GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

Guidotti, Alessandro; Auta, James; Davis, John M.; Dong, Erbao; Grayson, Dennis R.; Veldić, Marin; Zhang, Xianquan; Costa, E.

doi:10.1007/s00213-005-2212-8

Cited by 244 publications

(130 citation statements)

References 96 publications

(180 reference statements)

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“…Our findings point to alterations in glutamate recycling, glutamate receptors, GABA receptors, and glial cells and open up new possibilities for treating depression and possibly other diseases sharing a common pathophysiology. Although further research is warranted to decipher whether the reduced elements of glutamatergic signaling systemrelated gene expression are a reflection of altered gene regulation leading to pathologic metabolism or more simply a reflection of diminished populations of glutamatergic neurons, they could provide pharmaceutical targets, specific to the biological defect, for drugs that modulate glutamate transporters or antagonize specific glutamate and GABA A subunits (6,9,43,44). …”

Section: Discussionmentioning

confidence: 99%

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Choudary

Molnar

Evans

et al. 2005

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

563

387

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Abnormalities in L-glutamic acid (glutamate) and GABA signal transmission have been postulated to play a role in depression, but little is known about the underlying molecular determinants and neural mechanisms. Microarray analysis of specific areas of cerebral cortex from individuals who had suffered from major depressive disorder demonstrated significant down-regulation of SLC1A2 and SLC1A3, two key members of the glutamate͞neutral amino acid transporter protein family, SLC1. Similarly, expression of L-glutamate-ammonia ligase, the enzyme that converts glutamate to nontoxic glutamine was significantly decreased. Together, these changes could elevate levels of extracellular glutamate considerably, which is potentially neurotoxic and can affect the efficiency of glutamate signaling. The astroglial distribution of the two glutamate transporters and L-glutamate-ammonia ligase strongly links glia to the pathophysiology of depression and challenges the conventional notion that depression is solely a neuronal disorder. The same cortical areas displayed concomitant up-regulation of several glutamate and GABA A receptor subunits, of which GABA A␣1 and GABAA␤3 showed selectivity for individuals who had died by suicide, indicating their potential utility as biomarkers of suicidality. These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression.bipolar disorder ͉ GABAA receptors ͉ glutamate transporters ͉ major depression ͉ suicide C linical depression, the phenotypic hallmark of the two leading mood disorders [major depressive disorder (MDD) and bipolar affective disorder (BPD)], is the most common psychiatric illness. It affects Ϸ121 million people worldwide, with 10-20% of women and 5-12% of men estimated to experience a depressive episode in any 1-year period, and with evidence of suicidality in 15% of those affected (ref.

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Section: Discussionmentioning

confidence: 99%

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Choudary

Molnar

Evans

et al. 2005

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

563

387

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“…Consequently, understanding the influence of the BLA on the synaptic plasticity of GABAergic elements in the hippocampus may be beneficial in helping to develop pharmacological strategies for the treatment of SZ and other psychotic disorders (54)(55)(56). …”

Section: Discussionmentioning

confidence: 99%

Regulation of synaptic plasticity in a schizophrenia model

Gisabella

Bolshakov

Beneš

2005

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

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The pathology of schizophrenia is characterized by increased hippocampal activity at baseline and during auditory hallucinations. Animal-model studies in which the flow of activity to the hippocampus is increased through decreased amygdalar GABAergic inhibition have shown alterations of hippocampal circuitry similar to schizophrenia, but the functional importance of this phenomenon remains unclear. We provide evidence of decreased hippocampal feed-forward and tonic GABA-mediated inhibition in this animal model, complementing increased hippocampal activity seen in neuroimaging and postmortem studies. We demonstrate that GABA dysfunction increases long-term potentiation through activation of the cholinergic system, offering a new mechanism for pharmacological strategies of this disorder.any lines of evidence indicate that memory processing in the hippocampus is modulated by the amygdala (1). Projections from the amygdaloid complex reach several hippocampal regions, providing various routes by which the amygdaloid complex may potentially influence hippocampal function (2, 3). Reports suggest that inputs from the amygdala to the hippocampus via two separate pathways, the indirect perforant path and the direct pathway to CA2͞CA3, are responsible for alteration of the circuitry in CA4, CA3, and CA2 and, to a lesser extent, CA1 (4, 5). Electrical stimulation of the basolateral amygdala (BLA) in anesthetized rats generates synaptic potentials in the dentate gyrus of the hippocampus, indicating that they are connected through neuronal projections (6). In addition, emotional experiences are shown to activate the BLA, which, in turn, either enhances or impairs hippocampal longterm potentiation (LTP) (7-9). Direct evidence demonstrating that neuronal inputs from the amygdala modulate hippocampal synaptic plasticity has come from lesions in the BLA that result in the decrease of LTP in the rat hippocampus (6).In the past 10 years, several studies have suggested that the relationship between the BLA and hippocampus may also contribute to the pathophysiology of schizophrenia (SZ) (10-12). For example, brain-imaging studies have demonstrated volume reductions in both regions of schizophrenics (13). Moreover, several postmortem studies have pointed to a deficit of GABAergic activity in SZ in cortical (14-17) and subcortical areas, particularly hippocampal sectors CA3 and CA2, which receive abundant projections from the BLA (18,19). There is also a report showing direct evidence of a decrease of high-affinity GABA uptake in the amygdala of the postmortem schizophrenic brain (20). It has been postulated that these changes might induce an increased outflow of excitatory activity from the amygdala to the hippocampus and induce alterations of hippocampal circuitry, particularly in GABAergic interneurons (18). Such changes could influence LTP (21, 22), perhaps contributing to emotional learning during adolescence, the period when the SZ phenotype is first manifest. To test this hypothesis, we have developed a ''partial'' rodent model,...

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“…This form of inhibition has been identified in the cerebellum (Brickley et al 1996), hippocampus (Stell and Mody 2002), striatum (Ade et al 2008) and thalamus (Cope et al 2005). Importantly, increasing evidence has uncovered not only some of the physiological roles of eGABA A Rs but also their involvement in diverse neurological and neuropsychiatric disorders (Belelli et al 2009;Hines et al 2012), including stroke (Clarkson et al 2011), epilepsy Di Giovanni et al 2011a), anxiety (Lydiard 2003), depression (Maguire et al 2005;Luscher et al 2011), schizophrenia (Guidotti et al 2005) and autism (Pizzarelli and Cherubini 2011).…”

Section: Introductionmentioning

confidence: 99%

GPCR Modulation of Extrasynapitic GABAA Receptors

Connelly

Errington

Yagüe

et al. 2014

Extrasynaptic GABAA Receptors

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γ-Aminobutyric acid type A (GABA A ) receptors (GABA A Rs), the main inhibitory neurotransmitter-gated ion channels in the central nervous system, are finely tuned by other neurotransmitters and endogenous ligands. The regulation of synaptic GABA A Rs (sGABA A Rs) by G protein-coupled receptors (GPCRs) has been well characterized and is known to occur either through the conventional activation of second-messenger signalling cascades by G proteins or directly by protein-protein coupling. In contrast, research on the modulation of extrasynaptic GABA A R (eGABA A Rs) is still in its infancy and it remains to be determined whether both of the above mechanisms are capable of controlling eGABA A R function. In this chapter, we summarize the available literature on eGABA A R modulation by GPCRs, including GABA B , serotonin (5-HT), dopamine (DA), noradrenaline (NA) and metabotropic glutamate (mGlu) receptors. Although at present these GPCRs-eGABA A Rs cross-talks have been investigated in a limited number of brain areas (i.e., thalamus, cerebellum, hippocampus, striatum), it is already evident that eGABA A Rs show a nucleus-and neuronal type-selective regulation by GPCRs that differs from that of sGABA A Rs. This distinct regulation of eGABA A Rs versus sGABA A Rs by GPCRs provides mechanisms for receptor adaptation in response

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GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

Cited by 244 publications

References 96 publications

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Regulation of synaptic plasticity in a schizophrenia model

GPCR Modulation of Extrasynapitic GABAA Receptors

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