Postmortem studies on mitochondria in schizophrenia

Abstract

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.

Keywords: Cytochrome oxidase; Electron microscopy; Neuropathology; Postmortem; Psychosis.

Figure 1

Electron micrograph of human striatum. Mitochondria (m) are shown in various subcellular locations. In the dendrite (den) at the top of the field, mitochondrial associated ER (MAM) is shown (curved black arrow) with ER (short black arrows) connecting to the adjacent mitochondrion. In the terminal (AT) synapsing on a spine (Sp) in the lower part of the field, mitochondrial derived vesicles (MDVs) are shown (white arrow with black outline) budding off of a mitochondrion. Scale bars = 0.5 μm. Figure is modified from Figure 2a in Somerville et al., 2011b.

Figure 2

Electron micrographs of human striatum. A) Control. B) Schizophrenia. Mitochondria (m) are shown in various subcellular locations. Abbreviations: s, spine; at, axon terminal; den, dendrite; ma, myelinated axon; solid arrows, synapses; dotted arrow, spine emerging from dendrite. Scale bars = 0.5 μm. Figure is modified from Figure 1 in Somerville et al., 2011b.

Figure 3

Schematic drawing of the cortical striatal nigral pathway showing mitochondrial abnormalities in each region in schizophrenia. Depending on the study, the entire structure or subdivisions within, were studied. The cortex is divided in layers for layer specific changes. Patch (circles) and matrix compartments are shown for the caudate and putamen when abnormalities are striosome or matrix specific. The core and shell (hatched) of the nucleus accumbens are depicted. Mito, mitochondria. ROS, reactive oxygen species. NAA, N-acetylaspartate. COX, cytochrome oxidase. ETC, electron transport chain. Mito/synapse, mitochondria per terminal forming a synapse. T-resp, treatment responsive schizophrenia. AT, axon terminals. DA, dopamine. mtDNA, mitochondrial DNA. 1) Roberts et al., 2015; 2) Barksdale, et al., 2014; 3) Wang et al., 1999; 4) Reid et al., 2010; 5) Uranova et al., 2007, Vikhreva et al., 2016; 6) Mamdani et al., 2014; 7) Somerville et al., 2011; 8) Somerville et al., 2012; 9) Maurer et al., 2001; Ben-Shakar & Karry, 2008; 10) Cavalier et al., 1995; Prince et al., 1999, ; 11) Uranova et al., 1996, ; 12) Kung & Roberts, 1999; 13) McCollum et al., 2015; 14) Kolomeets & Uranova, 1999; 15) Walker & Roberts, 2016; 16) Rice et al., 2014.