Dopamine receptor signaling molecules are altered in elderly schizophrenic cortex

Baracskay, Karen L.; Haroutunian, Vahram; Meador‐Woodruff, James H.

doi:10.1002/syn.20292

Cited by 54 publications

(31 citation statements)

References 51 publications

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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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137

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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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

Self Cite

137

102

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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: 93%

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Sweet

Henteleff

Zhang

et al. 2008

Neuropsychopharmacol

259

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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“…One report found that DARPP-32 protein abundance was selectively reduced in the prefrontal cortex of brain tissue from patients with schizophrenia (19), and 1 recent report found no significant difference in mRNA levels in brains from 16 elderly schizophrenic patients compared with matched controls (20). However, given the central role of the protein in molecular mechanisms related to dopaminergic neurotransmission in striatum and its diverse pharmacological actions, we hypothesized that it would be associated in humans with higher-level cognitive and emotional behaviors implicated in cortical-striatal circuitry and function and contribute genetically to variation in these functions.…”

Section: Introductionmentioning

confidence: 98%

Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition

Meyer‐Lindenberg¹,

Straub²,

Lipska³

et al. 2007

J. Clin. Invest.

216

170

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Dopamine-and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.Introduction Dopamine-and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) was initially identified as a major target for dopamine-activated adenylyl cyclase in striatum (1). DARPP-32 acts as an amplifier of PKA-and PKG-mediated signaling when it is phosphorylated at Thr34, which converts it into an inhibitor of a multifunctional serine/threonine protein phosphatase, PP-1 (2). Conversely, phosphorylation at Thr75 by Cdk5 converts DARPP-32 into an inhibitor of PKA. Over more than 2 decades, an intense research effort has demonstrated that this dual function places DARPP-32 at a unique position as a central molecular switch, integrating multiple information streams and converging through a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones onto dopaminoceptive neurons (3). Since dopaminergic neurotransmission is critical for motivated behavior, working memory (4), and reward-related learning (5) and is implicated in, among other conditions, schizophrenia (6), alcoholism (7), Parkinson disease, and pathological gambling (8), DARPP-32 has received considerable attention not only in basic neuroscience but also in studies of the pathogenesis of these disorders and as a potential drug target. It has been shown that DARPP-32 mediates effects of D2 receptor stimulation (3), functions as a key node in a final common pathway of psychotomimetics in both frontal cortex and striatum (9), and is implicated in the mechanism of action of drugs of abuse (10).

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Dopamine receptor signaling molecules are altered in elderly schizophrenic cortex

Cited by 54 publications

References 51 publications

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

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

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition

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