Dopaminergic Abnormalities in Select Thalamic Nuclei in Schizophrenia: Involvement of the Intracellular Signal Integrating Proteins Calcyon and Spinophilin

Clinton, Sarah M.; Ibrahim, Hisham M.; Frey, Kirk A.; Davis, Kenneth L.; Haroutunian, Vahram; Meador‐Woodruff, James H.

doi:10.1176/appi.ajp.162.10.1859

Cited by 46 publications

(25 citation statements)

References 66 publications

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“…Examinations of spinophilin mRNA expression have yielded mixed results. Elevations in spinophilin mRNA across all cortical layers in PFC were reported in one study (Baracskay et al, 2006), whereas no change expression has been reported in anterior cingulate cortex in the same subjects (Baracskay et al, 2006) and in thalamus from the same brain tissue collection (Clinton et al, 2005). A study of PFC in a different cohort found no change in spinophilin mRNA expression in subjects with schizophrenia (Weickert et al, 2004).…”

Section: Interpretive Issuesmentioning

confidence: 89%

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Sweet

Henteleff

Zhang

et al. 2008

Neuropsychopharmacol

256

221

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We have previously identified reductions in mean pyramidal cell somal volume in deep layer 3 of BA 41 and 42 and reduced axon terminal density in deep layer 3 of BA 41. In other brain regions demonstrating similar deficits, reduced dendritic spine density has also been identified, leading us to hypothesize that dendritic spine density would also be reduced in BA 41 and 42. Because dendritic spines and their excitatory inputs are regulated in tandem, we further hypothesized that spine density would be correlated with axon terminal density. We used stereologic methods to quantify a marker of dendritic spines, spinophilin-immunoreactive (SP-IR) puncta, in deep layer 3 of BA 41 and 42 of 15 subjects with schizophrenia, each matched to a normal comparison subject. The effect of long-term haloperidol exposure on SP-IR puncta density was evaluated in nonhuman primates. SP-IR puncta density was significantly lower by 27.2% in deep layer 3 of BA 41 in the schizophrenia subjects, and by 22.2% in deep layer 3 of BA 42. In both BA 41 and 42, SP-IR puncta density was correlated with a marker of axon terminal density, but not with pyramidal cell somal volume. SP-IR puncta density did not differ between haloperidol-exposed and control monkeys. Lower SP-IR puncta density in deep layer 3 of BA 41 and 42 of subjects with schizophrenia may reflect concurrent reductions in excitatory afferent input. This may contribute to impairments in auditory sensory processing that are present in subjects with schizophrenia.

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Section: Interpretive Issuesmentioning

confidence: 89%

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Sweet

Henteleff

Zhang

et al. 2008

Neuropsychopharmacol

256

221

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“…For example, decreased DARPP-32 was detected in the frontal cortex and thalamus (Albert et al, 2002;Feldcamp et al, 2008;Ishikawa et al, 2007;Torres et al, 2009;Zhan et al, 2011), whereas transcripts for calcyon and spinophilin, mediators of dopaminergic signal integration, were increased in the thalamus in schizophrenia (Baracskay et al, 2006;Clinton et al, 2005). Additionally, phosphorylation of the N-methyl-D-aspartic acid (NMDA) receptor type 1 subunit at S897, a target of PKA, is decreased in the frontal cortex, suggesting fewer NMDA receptors at the synapse (Emamian et al, 2004;Tingley et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

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132

102

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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“…Calcyon is a single transmembrane protein expressed in brain [1;2] that has been linked to neuropsychiatric disorders such as schizophrenia in which expression of this protein is upregulated in the prefrontal cortex (PFC) and thalamus [3][4][5][6]. Recent molecular studies indicate that calcyon primarily interacts with clathrin light chain and enhances clathrin-mediated endocytosis (CME) [7].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

Trantham-Davidson¹,

Vazdarjanova²,

Dai³

et al. 2008

Behavioural Brain Research

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Gene linkage and association studies have implicated the region of chromosome 10q containing the calcyon locus with attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia susceptibility. In addition, levels of calcyon protein and transcripts are also significantly increased in postmortem tissue from schizophrenic brains. But whether altered calcyon expression might be part of the disease etiology or merely a patho-physiological side effect is not known. To begin to address this issue, we generated a transgenic mouse line (Cal OE ) using the human calcyon cDNA in which calcyon expression is up-regulated in a number of forebrain structures including the hippocampus, prefrontal cortex, striatum, and amygdala. Compared to control littermates, the Cal OE mice display a range of abnormal behaviors including spontaneous hyperactivity, reduced anxiety, and/or impaired restraint (harm avoidance) that would indicate that calcyon up-regulation leads to deficits in control over behavioral output.

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Dopaminergic Abnormalities in Select Thalamic Nuclei in Schizophrenia: Involvement of the Intracellular Signal Integrating Proteins Calcyon and Spinophilin

Abstract: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.

Cited by 46 publications

References 66 publications

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

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