Search

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular m

Background The single nucleotide polymorphism (SNP) rs1344706 [A > C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. Methods Using both univariate (voxel-based morphometry, VBM; cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy individuals selected from the Australian Schizophrenia Research Bank. Results Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy individuals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri; (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis/precentral gyrus; and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. Conclusions Contrary to some – but not all – previous findings, this study of a large sample of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in sample sizes and ethnicities may account for discrepant findings between the present and previous studies.

© 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins The neurotransmitter disturbances responsible for cognitive dysfunction in schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold proteins. We have recently reported that protein levels of FRMPD4, a multiscaffolding protein that modulates both Homer1 and postsynaptic density protein 95 activity, is altered in the schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with schizophrenia. We selected and examined a novel single nucleotide polymorphism, rs5979717 (positioned in the noncoding 3′ untranslated region of FRMPD4 and potentially influencing protein expression), for its association with schizophrenia and nine measures of cognitive function, using age-matched and sex-matched samples from 268 schizophrenia cases and 268 healthy controls. Brain samples from 20 schizophrenia patients and 20 healthy controls were additionally genotyped to study the influence of this variant on protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with schizophrenia in females (χ=4.52, P=0.030). No effects of rs5979717 were observed on cognitive performance, nor an influence of rs5979717 genotypes on the expression of FRMPD4 proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in schizophrenia, which now warrants further investigation.

Purpose: Schizophrenia is a complex neuropsychiatric disorder whereby symptoms present at adolescence. It is hypothesised the etiology of schizophrenia is due to NMDA receptor (NMDAR) hypofunction. Metabotropic glutamate 5 receptor (mGluR5) positive allosteric modulator (PAM) drugs are being investigated as a novel treatment of schizophrenia as an indirect manner to up-regulate NMDAR activity. We investigated the potential of subchronic adolescent CDPPB (an mGluR5 PAM) administration, to attenuate perinatal phencyclidine (PCP)-induced neurotransmission deficits. Methods: Male rat pups (n=6/group) were treated with PCP (10mg/kg) or saline on postnatal days (PN) 7, 9 and 11. Adolescent male rats (PN28) were administered with daily CDPPB (30mg/ kg) injections for seven consecutive days (PN28-34) and euthanased on PN35. Subsequently [3H]MK-801 and [3H]MPEP radioligand binding were performed on brain sections corresponding to the pre-frontal cortex, striatum, thalamus, and hippocampus. Results: No significant differences were observed in NMDAR binding between any of the treatment groups in all brain regions examined. However mGluR5 binding density was significantly reduced by 31% in the ventral hippocampus of the PCP/ CDPPB treated group compared to the saline control group (p=0.034). Similarly, mGluR5 binding density was significantly reduced by 49% in the striatum of the PCP/CDPPB treated group compared to the saline control group (p=0.01) and by 41% compared to the PCP/vehicle group (p=0.011). Conclusion: This study shows adolescent subchronic administration of CDPPB (30mg/kg) to have brain region specific effects on neurotransmission. Though we found reductions in mGluR5 binding density in CDPPB treated groups, this was not reflected in NMDAR binding density. Further investigation may prove this model a potential prevention tool to attenuate NMDAR hypofunction deficits.

Purpose: Metabotropic glutamate receptors (mGluRs) are proposed novel therapeutic targets for a variety of brain disorders such as schizophrenia (SZ), bipolar disorder (BP) and major depression (MD). Despite their potential, the involvement of these receptors in these pathological processes is uncertain. This information is crucial to understand the efficiency of drugs that target these receptors. Methods: Using post-mortem human brains, mGluR2/3 and mGluR5 binding densities were measured in the anterior cingulate cortex of SZ, BP, MD and matched controls (CT) (n=15/group) by receptor autoradiography. Results: Whilst preliminary analyses indicated no diagnostic effect in mGluR2/3 or mGluR5 binding densities, mGluR2/3 binding negatively correlated with age at death in the CT (r=-0.695, p=0.004) and SZ (r=- 0.528, p=0.043) groups, but not MD or BP. Contrarily, mGluR5 displayed a borderline positive correlation with age at death in SZ (r=0.505, p=0.055) and MD (r=-0.453, p=0.090) subjects. Furthermore, mGluR2/3 and mGluR5 binding correlated in subjects with SZ (r=-0.516, p=0.049), but not BP, MD or CT groups. Conclusion: Targeting mGluRs may provide a therapeutic mechanism to modulate glutamatergic activity in psychiatric disorders. Our findings of unaltered levels of mGluRs in SZ, BD, and MD may be beneficial by potentially providing an unhindered therapeutic target. However the association between age and both mGluR2/3 and mGluR5 binding in SZ subjects may have age-dependant therapeutic implications for the use of these drugs in SZ patients. There are no published investigations examining mGluR function, which may be integral to interpreting absence of change in mGluR protein levels.

Purpose: Metabotropic glutamate receptors (mGluRs) are proposed novel therapeutic targets for a variety of brain disorders such as schizophrenia (SZ), bipolar disorder (BP) and major depression (MD). Despite their potential, the involvement of these receptors in these pathological processes is uncertain. This information is crucial to understand the efficiency of drugs that target these receptors. Methods: Using post-mortem human brains, mGluR2/3 and mGluR5 binding densities were measured in the anterior cingulate cortex of SZ, BP, MD and matched controls (CT) (n=15/group) by receptor autoradiography. Results: Whilst preliminary analyses indicated no diagnostic effect in mGluR2/3 or mGluR5 binding densities, mGluR2/3 binding negatively correlated with age at death in the CT (r=-0.695, p=0.004) and SZ (r=- 0.528, p=0.043) groups, but not MD or BP. Contrarily, mGluR5 displayed a borderline positive correlation with age at death in SZ (r=0.505, p=0.055) and MD (r=-0.453, p=0.090) subjects. Furthermore, mGluR2/3 and mGluR5 binding correlated in subjects with SZ (r=-0.516, p=0.049), but not BP, MD or CT groups. Conclusion: Targeting mGluRs may provide a therapeutic mechanism to modulate glutamatergic activity in psychiatric disorders. Our findings of unaltered levels of mGluRs in SZ, BD, and MD may be beneficial by potentially providing an unhindered therapeutic target. However the association between age and both mGluR2/3 and mGluR5 binding in SZ subjects may have age-dependant therapeutic implications for the use of these drugs in SZ patients. There are no published investigations examining mGluR function, which may be integral to interpreting absence of change in mGluR protein levels.

Purpose: Schizophrenia is a complex neuropsychiatric disorder whereby symptoms present at adolescence. It is hypothesised the etiology of schizophrenia is due to NMDA receptor (NMDAR) hypofunction. Metabotropic glutamate 5 receptor (mGluR5) positive allosteric modulator (PAM) drugs are being investigated as a novel treatment of schizophrenia as an indirect manner to up-regulate NMDAR activity. We investigated the potential of subchronic adolescent CDPPB (an mGluR5 PAM) administration, to attenuate perinatal phencyclidine (PCP)-induced neurotransmission deficits. Methods: Male rat pups (n=6/group) were treated with PCP (10mg/kg) or saline on postnatal days (PN) 7, 9 and 11. Adolescent male rats (PN28) were administered with daily CDPPB (30mg/ kg) injections for seven consecutive days (PN28-34) and euthanased on PN35. Subsequently [3H]MK-801 and [3H]MPEP radioligand binding were performed on brain sections corresponding to the pre-frontal cortex, striatum, thalamus, and hippocampus. Results: No significant differences were observed in NMDAR binding between any of the treatment groups in all brain regions examined. However mGluR5 binding density was significantly reduced by 31% in the ventral hippocampus of the PCP/ CDPPB treated group compared to the saline control group (p=0.034). Similarly, mGluR5 binding density was significantly reduced by 49% in the striatum of the PCP/CDPPB treated group compared to the saline control group (p=0.01) and by 41% compared to the PCP/vehicle group (p=0.011). Conclusion: This study shows adolescent subchronic administration of CDPPB (30mg/kg) to have brain region specific effects on neurotransmission. Though we found reductions in mGluR5 binding density in CDPPB treated groups, this was not reflected in NMDAR binding density. Further investigation may prove this model a potential prevention tool to attenuate NMDAR hypofunction deficits.

Purpose: Schizophrenia is a complex neuropsychiatric disorder whereby symptoms present at adolescence. It is hypothesised the etiology of schizophrenia is due to NMDA receptor (NMDAR) hypofunction. Metabotropic glutamate 5 receptor (mGluR5) positive allosteric modulator (PAM) drugs are being investigated as a novel treatment of schizophrenia as an indirect manner to up-regulate NMDAR activity. We investigated the potential of subchronic adolescent CDPPB (an mGluR5 PAM) administration, to attenuate perinatal phencyclidine (PCP)-induced neurotransmission deficits. Methods: Male rat pups (n=6/group) were treated with PCP (10mg/kg) or saline on postnatal days (PN) 7, 9 and 11. Adolescent male rats (PN28) were administered with daily CDPPB (30mg/ kg) injections for seven consecutive days (PN28-34) and euthanased on PN35. Subsequently [3H]MK-801 and [3H]MPEP radioligand binding were performed on brain sections corresponding to the pre-frontal cortex, striatum, thalamus, and hippocampus. Results: No significant differences were observed in NMDAR binding between any of the treatment groups in all brain regions examined. However mGluR5 binding density was significantly reduced by 31% in the ventral hippocampus of the PCP/ CDPPB treated group compared to the saline control group (p=0.034). Similarly, mGluR5 binding density was significantly reduced by 49% in the striatum of the PCP/CDPPB treated group compared to the saline control group (p=0.01) and by 41% compared to the PCP/vehicle group (p=0.011). Conclusion: This study shows adolescent subchronic administration of CDPPB (30mg/kg) to have brain region specific effects on neurotransmission. Though we found reductions in mGluR5 binding density in CDPPB treated groups, this was not reflected in NMDAR binding density. Further investigation may prove this model a potential prevention tool to attenuate NMDAR hypofunction deficits.

Purpose: Metabotropic glutamate receptors (mGluRs) are proposed novel therapeutic targets for a variety of brain disorders such as schizophrenia (SZ), bipolar disorder (BP) and major depression (MD). Despite their potential, the involvement of these receptors in these pathological processes is uncertain. This information is crucial to understand the efficiency of drugs that target these receptors. Methods: Using post-mortem human brains, mGluR2/3 and mGluR5 binding densities were measured in the anterior cingulate cortex of SZ, BP, MD and matched controls (CT) (n=15/group) by receptor autoradiography. Results: Whilst preliminary analyses indicated no diagnostic effect in mGluR2/3 or mGluR5 binding densities, mGluR2/3 binding negatively correlated with age at death in the CT (r=-0.695, p=0.004) and SZ (r=- 0.528, p=0.043) groups, but not MD or BP. Contrarily, mGluR5 displayed a borderline positive correlation with age at death in SZ (r=0.505, p=0.055) and MD (r=-0.453, p=0.090) subjects. Furthermore, mGluR2/3 and mGluR5 binding correlated in subjects with SZ (r=-0.516, p=0.049), but not BP, MD or CT groups. Conclusion: Targeting mGluRs may provide a therapeutic mechanism to modulate glutamatergic activity in psychiatric disorders. Our findings of unaltered levels of mGluRs in SZ, BD, and MD may be beneficial by potentially providing an unhindered therapeutic target. However the association between age and both mGluR2/3 and mGluR5 binding in SZ subjects may have age-dependant therapeutic implications for the use of these drugs in SZ patients. There are no published investigations examining mGluR function, which may be integral to interpreting absence of change in mGluR protein levels.