Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 Tesla, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, myo-inositol, GABA, glutathione or other metabolites. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia.

Section: Discussionsupporting

confidence: 90%

Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7Tesla

Brandt

Unschuld

Pradhan

et al. 2016

“…These broad array of findings, which reveal decreases in the same proteins quantified in our study, support that altered synaptic connectivity in multiple brain regions may be a hallmark of schizophrenia. Although many of these findings have been replicated, other studies have failed to find differences in other brain regions in implicated in schizophrenia (Barksdale et al, 2014; Gray et al, 2010; Halim et al, 2003; Vawter et al, 2002; Young et al, 1998). One reason for the divergence of these findings may be that, while widespread, synaptic deficits may still be localized to discrete brain regions and cell types within them.…”

Section: Discussionmentioning

confidence: 98%

Molecular evidence for decreased synaptic efficacy in the postmortem olfactory bulb of individuals with schizophrenia

Egbujo

Sinclair

Borgmann‐Winter

et al. 2015

Multiple lines of evidence suggest altered synaptic plasticity/connectivity as a pathophysiologic mechanism for various symptom domains of schizophrenia. Olfactory dysfunction, an endophenotype of schizophrenia, reflects altered activity of the olfactory circuitry, which conveys signals from olfactory receptor neurons to the olfactory cortex via synaptic connections in the glomeruli of the olfactory bulb. The olfactory system begins with intranasal olfactory receptor neuron axons synapsing with mitral and tufted cells in the glomeruli of the olfactory bulb, which then convey signals directly to the olfactory cortex. We hypothesized that olfactory dysfunction in schizophrenia is associated with dysregulation of synaptic efficacy in the glomeruli of the olfactory bulb. To test this, we employed semi-quantitative immunohistochemistry to examine the olfactory bulbs of 13 postmortem samples from schizophrenia and their matched control pairs for glomerular expression of 5 pre- and postsynaptic proteins that are involved in the integrity and function of synapses. In the glomeruli of schizophrenia cases compared to their matched controls, we found significant decreases in three presynaptic proteins which play crucial roles in vesicular glutamate transport- synapsin IIa (−18.05%, p= 0.019), synaptophysin (−24.08% p=0.0016) and SNAP-25 (−23.9%, p=0.046). Two postsynaptic proteins important for spine formation and glutamatergic signaling were also decreased- spinophilin (−17.40%, p=0.042) and PSD-95 (−34.06%, p=0.015). These findings provide molecular evidence for decreased efficacy of synapses within the olfactory bulb, which may represent a synaptic mechanism underlying olfactory dysfunction in schizophrenia.

“…Oxidative stress, a result of mitochondrial production of reactive oxygen species, is increased (Wang et al, 2009). In a recent study markers of synapses and mitochondria were examined in the ACC in a schizophrenia cohort divided by treatment response (Barksdale et al, 2014). Protein levels of the mitochondrial marker, mitofusin-2, were normal in schizophrenia cases; moreover, there were no effects of treatment response.…”

Section: Mitochondrial Abnormalities In Schizophreniamentioning

confidence: 99%

Postmortem studies on mitochondria in schizophrenia

Roberts

2017

The aim of this paper is to provide a brief review of mitochondrial structure as it relates to function and then present abnormalities in mitochondria in postmortem schizophrenia with a focus on ultrastructure. Function, morphology, fusion, fission, motility, ΔΨmem, ATP production, mitochondrial derived vesicles, and mitochondria-associated ER membranes will be briefly covered. Pathology in mitochondria has long been implicated in schizophrenia, as shown by genetic, proteomic, enzymatic and anatomical abnormalities. The cortex and basal ganglia will be reviewed. In the anterior cingulate cortex, the number of mitochondria per neuronal somata in layers 5/6 in schizophrenia is decreased by 43%. There are also fewer mitochondria in terminals forming axospinous synapses. In the caudate and putamen the number of mitochondria is abnormal in both glial cells and neurons in schizophrenia subjects, the extent of which depends on treatment, response and predominant lifetime symptoms. Treatment-responsive schizophrenia subjects had about a 40% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen, while treatment resistant cases had normal values. A decrease in mitochondrial density in the neuropil distinguishes paranoid from undifferentiated schizophrenia. The appearance, size and density of mitochondria were normal in the nucleus accumbens. In the substantia nigra, COX subunits were affected in rostral regions. Mitochondrial hyperplasia occurs within axon terminals that synapse onto dopamine neurons, but mitochondria in dopamine neuronal somata are similar in size and number. In schizophrenia, mitochondria are differentially affected depending on the brain region, cell type, subcellular location, treatment status, treatment response and symptoms.