Antipsychotics increase microtubule‐associated protein 2 mRNA but not spinophilin mRNA in rat hippocampus and cortex

Law, Amanda J.; Hutchinson, Louise J.; Burnet, Philip W.J.; Harrison, Paul J.

doi:10.1002/jnr.20092

Cited by 29 publications

(24 citation statements)

References 66 publications

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“…In agreement with previous reports in rats (Law et al, 2004a) and humans (Law et al, 2004b), the distribution of spinophilin mRNA in mutant and wild type mice was consistent with a dendritic localization, with labelling observed not only over the pyramidal cell layer, but also adjacent strata of the DG and Ammon's horn. Genotype (F 2, 110 =22.28, P<0.001) had a significant effect upon spinophilin mRNA in the overall ANOVA, and there was a significant genotype by area interaction (F 14, 110 =4.03, P<0.001).…”

Section: Spinophilin Mrnasupporting

confidence: 92%

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

et al. 2006

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proteins, was quantified in female STOP null (n=7), heterozygous (n=5) and wild type (n=6) mice. For STOP null and heterozygous mice, synaptophysin, VGlut1, GAP-43 and spinophilin mRNAs were decreased in the hippocampus, whilst in addition in the null mice, synaptophysin, VGlut1 and spinophilin mRNAs were decreased in the cerebellum. Alterations in synaptic protein mRNA expression were also detected in the frontal and occipital cortex.MAP2 mRNA expression was unchanged in all brain regions. The profile of mRNA changes is broadly similar to that observed in schizophrenia. Together the data provide supporting evidence for a role for microtubules in synaptic function, and suggest that STOP, or other microtubule proteins, may contribute to the synaptic pathology of schizophrenia.

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Section: Spinophilin Mrnasupporting

confidence: 92%

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

et al. 2006

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“…These findings appear to be consistent with a previous report that the expression of spinophilin mRNA, a protein present in most dendritic spines, was unchanged in rats exposed to antipsychotic medications. 33 Second, the observed decrease in mRNA expression in the subjects with schizophrenia does not appear to reflect a general decline in RNA integrity in these subjects because (1) their brain pH and RIN values were in the range known to be associated with sudden death and good RNA preservation 30 and (2) similar studies in the same subjects with schizophrenia demonstrated no differ- Figure 2 Representative film autoradiograms illustrating the expression of Cdc42, Rac1, RhoA, Duo and drebrin mRNAs in DLPFC area 9 of a control subject and an age-, sex-and PMI-matched subject with schizophrenia. The intensities of the hybridization signals are presented in pseudocolor manner according to the calibration scales (right) for each mRNA.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia

2006

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Postmortem studies have revealed reduced densities of dendritic spines in the dorsal lateral prefrontal cortex (DLPFC) of subjects with schizophrenia. However, the molecular mechanisms that might contribute to these alterations are unknown. Recent studies of the intracellular signals that regulate spine dynamics have identified members of the RhoGTPase family (e.g., Cdc42, Rac1, RhoA) as critical regulators of spine structure. In addition, Duo and drebrin are spine-specific proteins that are critical for spine maintenance and spine formation, respectively. In order to determine whether the mRNA expression levels of Cdc42, Rac1, RhoA, Duo or drebrin are altered in schizophrenia, tissue sections containing DLPFC area 9 from 15 matched pairs of subjects with schizophrenia and control subjects were processed for in situ hybridization. Expression levels of these mRNAs were also correlated with DLPFC spine density in a subset of the same subjects. In order to assess the potential influence of antipsychotic medications on the expression of these mRNAs, similar studies were conducted in monkeys chronically exposed to haloperidol or olanzapine. The expression of each of these mRNAs was lower in the gray matter of the subjects with schizophrenia compared to the control subjects, although only the reductions in Cdc42 and Duo remained significant after corrections for multiple comparisons. In addition, spine density was strongly correlated with the expression levels of both Duo (r = 0.73, P = 0.007) and Cdc42 (r = 0.71, P = 0.009) mRNAs. In contrast, the expression levels of Cdc42 and Duo mRNAs were not altered in monkeys chronically exposed to antipsychotic medications. In conclusion, reduced expression of Cdc42 and Duo mRNAs may represent molecular mechanisms that contribute to the decreased density of dendritic spines in the DLPFC of subjects with schizophrenia.

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“…Several studies have examined the effect of antipsychotic exposure on spinophilin mRNA or protein expression. Law et al (2004a) reported no change in spinophilin mRNA expression in occipitoparietal cortex and hippocampus of rats after 14 days of daily exposure to chlorpromazine 15 mg/kg, haloperidol 1 mg/kg, clozapine 25 mg/kg, olanzapine 5 mg/kg, or risperidone 0.5 mg/kg. Kabbani and Levenson (2006) examined mice exposed for 16 days to daily haloperidol 3 mg/kg or clozapine 4 mg/kg.…”

Section: Effect Of Antipsychotic Treatmentmentioning

confidence: 96%

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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Antipsychotics increase microtubule‐associated protein 2 mRNA but not spinophilin mRNA in rat hippocampus and cortex

Cited by 29 publications

References 66 publications

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

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