Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder

Guidotti, Alessandro; Auta, James; Davis, John M.; Gerevini, Valeria DiGiorgi; Dwivedi, Yogesh K.; Grayson, Dennis R.; Impagnatiello, Francesco; Pandey, Ghanshyam N.; Pesold, Christine; Sharma, Rajiv P.; Uzunov, Doncho P.; Costa, E.

doi:10.1001/archpsyc.57.11.1061

Cited by 1,136 publications

(896 citation statements)

References 34 publications

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“…Interestingly, these extended TUJ1‐positive structures showed distinct GAD67‐positive protrusions, dendritic spines of inhibitory GABAergic nature suggesting that our in vitro differentiating conditions are physiological (Guidotti et al , 2000). …”

Section: Resultsmentioning

confidence: 89%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

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A mutation in the centrosomal‐P4.1‐associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms of NPCs maintenance remain unclear. Here, we report an unexpected role for the cilium in NPCs maintenance and identify CPAP as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, and OFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutated CPAP fails to localize at the ciliary base associated with inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re‐entry leading to premature differentiation of patient iPS‐derived NPCs. Aberrant CDC function also promotes premature differentiation of NPCs in Seckel iPS‐derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control.

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Section: Resultsmentioning

confidence: 89%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

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“…More recently, a decrease in GAD 67 mRNA, but not GAD 65 , expression has again been noted (Guidotti et al 2000). A variety of studies have suggested that GAD 67 is regulated through transcriptional mechanism.…”

Section: Postmortem Evidence For a Gaba Defect In Schizophreniamentioning

confidence: 96%

“…Since mRNA for the two isoforms of GAD are expressed by 95% of the neurons in rat hippocampus (Stone et al 1999), it seems likely that complex cellular mechanisms may be influencing the nature of the results observed in these postmortem studies. The fact that changes in GAD 67 mRNA have been observed not only in schizophrenics, but also in subjects with bipolar disorder (Guidotti et al 2000;Heckers et al 2001) suggests that these changes may be related to a nonspecific factor associated with both disorders. Interestingly, differential expression of mRNAs associated with the two isoforms of GAD have been reported in relation to both acute and chronic stress (Bowers et al 1998), although in this case that for GAD 67 was increased, rather than decreased as it is in schizophrenia and bipolar disorder.…”

Section: Postmortem Evidence For a Gaba Defect In Schizophreniamentioning

confidence: 99%

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Beneš

Berretta

2001

Neuropsychopharmacology

996

643

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Neurons that express the compound, ␥ -aminobutyric acid (GABA), are broadly present throughout the central nervous system, although telencephalic structures, such as the cerebral cortex, show the most abundant quantities of this neurotransmitter (Jones 1987). In the discussion that follows, the anatomy and physiology of various types of GABAergic interneurons in the cortex and hippocampus will be discussed and related to recent postmortem studies implicating this transmitter system in the pathophysiology of schizophrenia and bi- 25 , NO . 1 polar disorder and their treatment with neuroleptic drugs (for more comprehensive reviews on cortical and hippocampal neurons see: Hof et al. 1993;Freund and Buzsaki 1996;Somogyi et al. 1998). NEUROBIOLOGY OF GABAERGIC INTERNEURONSBased on Golgi-impregnation studies, Ramon y Cajal provided the first descriptions of several different morphological subtypes of interneurons in the cerebral cortex and hippocampus (Ramon y Cajal 1893, 1911. In more recent years, it has been shown that, with some overlap, different morphological subtypes also have distinct distributions, connectivity, neurochemistry, and electrophysiological properties (for reviews see Hof et al. 1993;Freund and Buzsaki 1996). It is interesting to note that every segment of a pyramidal neuron, such as the soma, dendritic branches and spines, and the initial axonal segment, receives dense GABAergic synaptic innervation (O'Kusky and Colonnier 1982;Hendry et al. 1983;Houser et al. 1983; Beaulieu et al. 1992; for reviews see Jones 1993;Freund and Buzsaki 1996). Even more interestingly, each of these segments appears to be innervated by distinct GABAergic neuronal subtypes (see below).These differences strongly suggest that each of these subtypes plays a fundamentally different role in physiological and pathological mechanisms. In the discussion that follows, cortical interneurons will be described first, since our most basic understanding of GABAergic cells is derived from these populations. In more recent years, however, similar characterizations of interneurons in hippocampus have emerged. Although these cells show some striking similarities to their cortical counterparts, there are also some unique features that distinguish them. For this reason, interneurons in the hippocampus are discussed separately. Cortex Neuroanatomical Studies of Cortical Interneurons.Various types of GABAergic neurons can be categorized according to the type of synaptic profiles they are associated with, as this has direct implications for understanding the physiological role of these cells in cortical circuits. These categories are discussed below.A XO -S OMATIC I NHIBITORY S YNAPSES (B ASKET C ELLS ). The most commonly encountered interneurons ( Figure 1A) are multipolar in shape, i.e., they may have three or more primary dendritic branches emanating from their cell bodies, some having somata that are as large as those of pyramidal neurons (Jones and Hendry 1984). Using immunocytochemistry to localize the enzyme ). These cells also ...

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“…4 In nonhuman primates, normal working memory function depends on GABA-mediated circuitry in the DLPFC 5,6 and decreased levels of the mRNAs encoding the 67 kDa isoform of glutamic acid decarboxylase (GAD 67 ), an enzyme that synthesizes GABA, and GABA transporter 1 (GAT1), a presynaptic transporter for the reuptake of synaptically released GABA, have been replicated in multiple post-mortem studies of schizophrenia. [7][8][9][10][11][12][13] Indeed, an analysis of all post-mortem studies of schizophrenia conducted in specimens from the Stanley Neuropathology Consortium revealed that three genes expressed in GABA neurons (reelin, parvalbumin (PV) and GAD 67 ) had the most abnormal transcript and protein levels in schizophrenia. 14 At the cellular level, the density of neurons with detectable levels of GAD 67 mRNA was significantly decreased in schizophrenia subjects, 7,9 whereas in neurons with detectable levels of GAD 67 mRNA, the expression level per neuron did not differ from control values.…”

Section: Introductionmentioning

confidence: 99%

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

et al. 2007

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In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex-and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67 ) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA A receptor subunits (a1, a4, b3, c2 and d). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD 67 , SST and a1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCKcontaining subpopulations of GABA neurons and in the signaling via certain GABA A receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

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Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder

Cited by 1,136 publications

References 34 publications

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

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