Severe symptoms predict salivary interleukin-6, interleukin-1β, and tumor necrosis factor-α levels in children and youth with obsessive-compulsive disorder.

Objective: Childhood-onset obsessive-compulsive disorder (OCD) has been associated with immune dysregulation, including aberrant plasma inflammatory markers and increased rates of infectious and immune-mediated disorders. Saliva may provide a minimally-invasive tool for assessing oral mucosal immunity and inflammatory biomarkers in this population. The primary aim of this study was to compare salivary defense proteins and inflammatory mediators in saliva from children and youth with OCD and healthy controls, and evaluate their associations with measures of oral health and OCD phenotype.

Diffusion kurtosis imaging of white matter in bipolar disorder.

White matter pathology likely contributes to the pathogenesis of bipolar disorder (BD). Most studies of white matter in BD have used diffusion tensor imaging (DTI), but the advent of more advanced multi-shell diffusion MRI imaging offers the possibility to investigate other aspects of white matter microstructure. Diffusion kurtosis imaging (DKI) extends the DTI model and provides additional measures related to diffusion restriction.

Diminished levels of the chemokine fractalkine in post-mortem prefrontal cortex in schizophrenia but not bipolar disorder.

Objectives: Though the pathophysiology underlying schizophrenia (SCZ) and bipolar disorder (BD) is not fully understood, immune function may be dysregulated, with microglia, the brain's resident immune cells, implicated in this process. Signalling between the neuronal chemokine fractalkine (CX3CL1) and its microglial receptor CX3CR1 facilitates neuron-microglia interactions, influencing microglial activation and synaptic function. As such, alterations in fractalkine signalling may contribute to immune and synaptic alterations observed in SCZ and BD.

The SNAP25 Interactome in Ventromedial Caudate in Schizophrenia Includes the Mitochondrial Protein ARF1.

Abnormalities of SNAP25 (synaptosome-associated protein 25) amount and protein-protein interactions occur in schizophrenia, and may contribute to abnormalities of neurotransmitter release in patients. However, presynaptic terminal function depends on multiple subcellular mechanisms, including energy provided by mitochondria. To explore the SNAP25 interactome in schizophrenia, we immunoprecipitated SNAP25 along with interacting proteins from the ventromedial caudate of 15 cases of schizophrenia and 13 controls.

Reduced SNAP25 Protein Fragmentation Contributes to SNARE Complex Dysregulation in Schizophrenia Postmortem Brain.

Recent studies associated schizophrenia with enhanced functionality of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Altered degradation pathways of the three core SNARE proteins: synaptosomal-associated protein 25 (SNAP25), syntaxin-1 and vesicle-associated membrane protein (VAMP) could contribute to enhanced complex function. To investigate these pathways, we first identified a 15-kDa SNAP25 fragment (f-S25) in human and rat brains, highly enriched in synaptosomal extractions, and mainly attached to cytosolic membranes with low hydrophobicity.

Evidence for altered cell membrane lipid composition in postmortem prefrontal white matter in bipolar disorder and schizophrenia.

Brain imaging suggests that white matter abnormalities, including compromised white matter integrity in the frontal lobe, are shared across bipolar disorder (BD) and schizophrenia (SCZ). However, the precise molecular and cellular correlates remain to be elucidated. Given evidence for widespread alterations in cell membrane lipid composition in both disorders, we sought to investigate whether lipid composition is disturbed in frontal white matter in SCZ and BD.

Prefrontal fatty acid composition in schizophrenia and bipolar disorder: Association with reelin expression.

Objective: The extracellular matrix protein reelin regulates early brain development and synaptic plasticity in adulthood. Reelin is decreased in the postmortem brain in schizophrenia patients. Reelin's two receptors, ApoER2 and VLDLR, are also substrates for ApoE - a key lipoprotein that regulates phospholipid homeostasis in the brain.

Neuroadaptations to antipsychotic drugs: Insights from pre-clinical and human post-mortem studies.

Antipsychotic drugs, all of which block the dopamine D2 receptor to a greater or lesser extent, are the mainstay for the pharmacological treatment of schizophrenia. Engaging in a deeper understanding of how antipsychotics act on the brain and body, at the cellular, molecular and physiological level is vital to comprehend both the beneficial and potentially harmful actions of these medications and stimulate development of novel therapeutics. To address this, we review recent advances in our understanding of neuroadaptations to antipsychotics, focusing on (1) treatment efficacy, (2) impact on brain volume and (3) evidence from human post-mortem studies that attempt to dissect neuropathological effects of antipsychotic drugs from organic schizophrenia neurobiology and (4) cardio-metabolic side effects.

Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia.

Objectives: Brain imaging studies have implicated white matter dysfunction in the pathophysiology of both bipolar disorder (BD) and schizophrenia (SCZ). However, the contribution of axons to white matter pathology in these disorders is not yet understood. Maintenance of neuronal function is dependent on the active transport of biological material, including synaptic proteins, along the axon.

Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia.

SNAP-25 and syntaxin are presynaptic terminal SNARE proteins altered in amount and function in schizophrenia. In the ventral caudate, we observed 32% lower SNAP-25 and 26% lower syntaxin, but greater interaction between the two proteins using an in vitro assay. SNAP-25 has two isoforms, SNAP-25A and B, differing by only 9 amino acids, but with different effects on neurotransmission.

Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample.

Background: Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants.

Effects of haloperidol and clozapine administration on oxidative stress in rat brain, liver and serum.

Antipsychotics remain the standard of care for individuals with schizophrenia, despite their association with adverse effects including extrapyramidal symptoms, metabolic syndrome and agranulocytosis. While the biological mechanisms underlying these side effects remain unresolved, it has been proposed that oxidative stress may play a role in their development. The aim of this study was to evaluate markers of oxidative stress associated with first- and second-generation antipsychotics, focusing on protein and lipid oxidation and expression of the antioxidant proteins peroxiredoxin-2 and peroxiredoxin-6.

Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia.

Background: Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia.

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder.

Background: Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Increased expression of glial fibrillary acidic protein in prefrontal cortex in psychotic illness.

Astrocyte dysregulation has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD), however the exact nature of astrocytic alterations remains to be identified. In this study we investigated whether levels of four astrocyte-specific proteins; glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase 1L1 (ALDH1L1), vimentin and excitatory amino acid transporter 1 (EAAT1) are altered in SCZ and BPD. Relative concentrations of GFAP, ALDH1L1, vimentin and EAAT1 were assessed post-mortem in dorsolateral prefrontal cortex in SCZ (n=35), BPD (n=34) and non-psychiatric controls (n=35) by western blotting.

Increased hippocampal neurogenesis and p21 expression in depression: dependent on antidepressants, sex, age, and antipsychotic exposure.

The mammalian hippocampus continues to generate new neurons throughout life. The function of adult-generated neurons remains controversial, but adult neurogenesis in the hippocampus is related to depression. Studies show that neurogenesis in the hippocampus is regulated by antidepressants in both humans and rodents, but no studies have examined the effects of age, sex, or antipsychotic exposure on the relationship between depression, antidepressant exposure, and hippocampal neurogenesis in humans.

ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype.

Background: Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype.

Effects of sub-chronic clozapine and haloperidol administration on brain lipid levels.

Abnormal lipid profiles have been reported in the central nervous system (CNS) in individuals with schizophrenia, although the etiology of these changes remains to be elucidated. While treatment with second-generation antipsychotics has been associated with alterations in peripheral lipid levels and changes in erythrocyte membrane composition, the relationship between peripheral and CNS lipid levels is complex and the effect of antipsychotics on CNS lipid regulation is not yet understood. In this study we investigated whether sub-chronic administration of the second-generation antipsychotic clozapine and the first-generation antipsychotic haloperidol alters brain membrane lipid composition in male Sprague-Dawley rats.

A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia.

Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of protein-protein interactions are limited.

Two-dimensional assessment of cytoarchitecture in the superior temporal white matter in schizophrenia, major depressive disorder and bipolar disorder.

Evidence from brain imaging studies indicates that white matter volume, density and fractional anisotropy may be altered in individuals with schizophrenia and bipolar disorder. However, the molecular correlates of these deficits remain unknown. In this study we performed a cytoarchitectural assessment of the white matter adjacent to the planum temporale (PT), an auditory association region located within the superior temporal gyrus, in subjects with schizophrenia, bipolar disorder, major depressive disorder and controls (15 subjects per group).

Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia.

The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown.

Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease-associated changes.

Abnormalities of the anterior cingulate cortex have previously been described in schizophrenia, major depressive disorder and bipolar disorder. In this study 2-DE was performed followed by mass spectrometric sequencing to identify disease-specific protein changes within the anterior cingulate cortex in these psychiatric disorders. The 2-DE system comprised IPGs 4-7 and 6-9 in the first, IEF dimension and SDS-PAGE in the second dimension.

Reductions in cholesterol and synaptic markers in association cortex in mood disorders.

Objectives: Cholesterol forms an integral part of cell membranes and is a major component of myelin. Furthermore, cholesterol also plays a vital role in the development, function and stability of synapses. While low serum cholesterol has previously been associated with mood disorders, cholesterol levels have yet to be quantified within the brain in these disorders.