Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

Bitanihirwe, Byron K.Y.; Lim, Maribel P.; Kelley, Jon; Kaneko, Takeshi; Woo, T.U.W.

doi:10.1186/1471-244x-9-71

Cited by 122 publications

(89 citation statements)

References 90 publications

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“…For example, the density of dendritic spines and branches on layer 3, but not layer 5 pyramidal cells appears to be reduced in subjects with schizophrenia (Garey et al 1998;Glantz and Lewis 2000;Kalus et al 2000). Consistent with these findings, the somal area of layer 3 pyramidal cells (Pierri et al 2001) and the number of glutamatergic axon terminals in this layer, as visualized by vGluT1 (vesicular glutamate transporter 1) immunohistochemistry, have also been shown to be decreased in schizophrenia subjects (Bitanihirwe et al 2009). Because layer 3 pyramidal neurons furnish corticocortical connections that link the PFC to other cortical regions and because such large-scale networks are critical for the integrity of cognitive and perceptive functioning, disturbances of information processing carried out by circuits subserved by these neurons may contribute to a wide range of symptoms and cognitive deficits of the illness.…”

Section: Synaptic Connectivities In the Pfc Are Deficient In Schizophsupporting

confidence: 63%

“…In primary neuronal cultures, Kinney and colleagues have shown that NR2A expression in PV neurons is 5-fold greater than that in pyramidal cells (Kinney et al 2006), although it is unclear if this holds true in humans (Bitanihirwe et al 2009). Furthermore, NR2A, but not NR2B selective antagonist downregulates GAD 67 and PV expression in PV neurons (Kinney et al 2006).…”

Section: Deficient Glutamatergic Inputs May Contribute To the Dysfuncmentioning

confidence: 99%

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Neurobiology of Schizophrenia Onset

Woo¹

2013

The Neurobiology of Childhood

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The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood. Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experiencedependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness. Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC. In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning. Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing. As such, further characterization of these mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder. KeywordsCerebral cortex; Critical period; Dendritic spines; Extracellular matrix; GABA; Gamma band oscillation; Oxidative stress; Parvalbumin; Schizophrenia; Synaptic pruning Schizophrenia is a complex, prevalent, and extremely debilitating brain disorder affecting approximately 1% of the population worldwide. It is defined by a constellation of positive (i.e., delusions and hallucinations) and negative (i.e., affective flattening, avolition, alogia, anergia, and anhedonia) symptoms. In addition, patients exhibit prominent cognitive deficits, such as disturbances in executive functions, working memory, and attention. Together, these symptoms and cognitive deficits render the individuals inflicted with the

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Section: Synaptic Connectivities In the Pfc Are Deficient In Schizophsupporting

confidence: 63%

Section: Deficient Glutamatergic Inputs May Contribute To the Dysfuncmentioning

confidence: 99%

Neurobiology of Schizophrenia Onset

Woo¹

2013

The Neurobiology of Childhood

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“…PV cells mediate γ-band activity (8,9), and reduced PV immunoreactivity in inhibitory neurons is observed in schizophrenia (51)(52)(53). PV cells of the hippocampus are sparsely distributed, occurring primarily in stratum pyramidal, where they comprise up to 70% of the GABAergic neurons and a smaller portion of the interneurons in the adjoining areas of stratum oriens and stratum radiatum ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Carlson

Talbot²,

Halene³

et al. 2011

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

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DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.GABAergic | γ-oscillation | hippocampus | evoked response spectral perturbation | Sandy mouse P atients with schizophrenia have reduced amplitude and gating of auditory event-related potentials (ERPs) (1, 2). Recent clinical studies also show abnormal γ-band oscillations (30-100 Hz) as an endophenotype of the illness that is associated with reduced cognitive function (3-7). Work in animal models shows a prominent role of cortical inhibitory networks in generating γ-oscillations (8, 9), which in turn, supports the role of aberrant GABAergic inhibition as an important potential component of schizophrenia (4,7,10,11). The GABA-producing enzyme glutamic acid decarboxylase is dysregulated in schizophrenia, and postsynaptic GABA A receptors are dysregulated as well (4). Risk alleles for GABA A receptor subunits are also associated with the disease (12, 13), although linkage is weaker than the linkage found with dysbindin-1 and other candidate genes such as DISC1 (14). At the anatomical level, there is a loss of immunoreactivity for parvalbumin (PV) in schizophrenia. PV is a calcium-binding protein marker for a class of fast-spiking GABAergic neurons. It is debated whether reduced PV in postmortem studies is caused by reduction in cell number or merely loss of protein expression. In either case, reduced PV immunoreactivity suggests disruption of an important source of local circuit inhibition (4, 15).Although clinical electrophysiological and postmortem anatomical findings support the role of GABA dysfunction in schizophrenia, a larger set of schizophrenia risk haplotypes are thought to confer reduced NMDA receptor-mediated function and changes in glutamatergic transmission [e.g., DISC1; Neuregu...

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“…This present study is the first to use RNA interference to target the expression of VGLUT1 in a specific brain region in vivo as a novel means of manipulating synaptic glutamate release. Hippocampal expression of VGLUT1 mRNA and protein is decreased in schizophrenia (Eastwood and Harrison, 2005;Sawada et al, 2005;Piyabhan and Reynolds, 2006) and, although striatal deficits have also been reported (Piyabhan and Reynolds, 2006;Nudmamud-Thanoi et al, 2007), cortical changes (which do occur in depression; Gilabert-Juan et al, 2012) are far less robust in schizophrenia (Corti et al, 2007;OniOrisan et al, 2008;Uezato et al, 2009;Eastwood and Harrison, 2010) and appear restricted to specific layers of the prefrontal cortex (Eastwood and Harrison, 2005;Bitanihirwe et al, 2009), whereas the amygdala remains unaffected . The principal finding of the current study is that administration of a VGLUT1-targeting lentiviral shRNA vector into the dorsal hippocampus of Targeting whole-brain VGLUT1 expression using conventional gene knockout strategies results in a 35-41% decrease in transporter levels in heterozygous animals (Tordera et al, 2007;Garcia-Garcia et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

King

Kurian

Qin

et al. 2013

Neuropsychopharmacol

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Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.

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Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

Cited by 122 publications

References 90 publications

Neurobiology of Schizophrenia Onset

Neurobiology of Schizophrenia Onset

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

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