No abstract

Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

To test the hypothesis that muscarinic receptors are involved in the pathology of schizophrenia, we measured muscarinic 1 (M1R) and muscarinic 4 (M4R) protein and mRNA as well as [ 3 H]pirenzepine binding in Brodmann's areas (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. There was a significant decrease in [ 3 H]pirenzepine binding to BA 9 (mean ± SEM: 151 ± 15 vs 195 ± 10 fmol mg −1 ETE; P Ͻ 0.02), but not BA 40 (143 ± 13 vs 166 ± 11 fmol mg −1 ETE), from subjects with schizophrenia. The level of M1R protein (0.11 ± 0.007 vs 0.15 ± 0.008 OD; P Ͻ 0.01), but not M4R protein, was decreased in BA9 from schizophrenic subjects with neither receptor protein being altered in BA 40. The level of M1R mRNA was decreased in BA 9 (30 ± 7.0 vs 79 ± 14 dpm × 10 3 mg −1 ETE, P Ͻ 0.01) and BA 40 (28 ± 5.9 vs 99 ± 14, P Ͻ 0.01) with schizophrenia but M4R mRNA was only decreased in BA 40 (48 ± 6.6 vs 89 ± 9.9, P Ͻ 0.005). These data suggest that the M1R, at least in the dorsolateral prefrontal cortex, may have a role in the pathology of schizophrenia.

Schizophrenia is widely acknowledged as being a syndrome, consisting of an undefined number of diseases probably with differing pathologies. Although studying a syndrome makes the identification of an underlying pathology more difficult; neuroimaging, neuropsychopharmacological and post-mortem brain studies all implicate muscarinic acetylcholine receptors (CHRM) in the pathology of the disorder. We have established that the CHRM1 is selectively decreased in the dorsolateral prefrontal cortex of subjects with schizophrenia. To expand this finding, we wanted to ascertain whether decreased cortical CHRMs might (1) define a subgroup of schizophrenia and/or (2) be related to CHRM1 genotype. We assessed cortical [ 3 H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex-matched control subjects. Kernel density estimation showed that [ 3 H]pirenzepine binding in BA9 divided the schizophrenia, but not control, cohort into two distinct populations. One of the schizophrenia cohorts, comprising 26% of all subjects with the disorder, had a 74% reduction in mean cortical [ 3 H]pirenzepine binding compared to controls. We suggest that these individuals make up 'muscarinic receptor-deficit schizophrenia' (MRDS). The MRDS could not be separated from other subjects with schizophrenia by CHRM1 sequence, gender, age, suicide, duration of illness or any particular drug treatment. Being able to define a subgroup within schizophrenia using a central biological parameter is a pivotal step towards understanding the biochemistry underlying at least one form of the disorder and may represent a biomarker that can be used in neuroimaging.

Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophreniaassociated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood World Journal of Psychiatry W J P oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.

Phospholipase C-b1 (PLC-b1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-b1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-b1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenialike symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-b1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.

Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.

We propose that the NMDA receptor signaling complex, including the intracellular machinery that is coupled to the NMDA receptor subunits, is abnormal in the hippocampus in bipolar disorder. These data suggest that bipolar disorder might be associated with abnormalities of glutamate-linked intracellular signaling and trafficking processes.