Mitochondrial Complex I Subunits are Altered in Rats with Neonatal Ventral Hippocampal Damage but not in Rats Exposed to Oxygen Restriction at Neonatal Age

Abstract

Several independent lines of evidence suggest mitochondrial dysfunction in schizophrenia in brain and periphery, including mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system, and altered mitochondrial-related gene expression. In an attempt to decipher whether mitochondrial complex I abnormality in schizophrenia is a core pathophysiological process or is attributable to medication, we studied two animal models of schizophrenia related to the neurodevelopmental hypothesis of this disorder. Protein levels of complex I subunits, 24, 51, and 75 kDa, were assessed in neonatal ventral hippocampal lesion rat model and in rats exposed to hypoxia at a neonatal age. In the prefrontal cortex, a major anatomical substrate of schizophrenia, neonatal ventral hippocampal lesion induced a significant prepubertal increase and postpubertal decrease in all three subunits of complex I as compared to sham-treated rats, while no change was observed in the cingulate cortex. Neonatal exposure to hypoxia did not affect protein levels of any of the three subunits in the prefrontal cortex. An age-dependent increase in the expression of complex I subunits was observed, which was distorted in the prefrontal cortex by the neonatal ventral hippocampal lesion. Complex I alterations in schizophrenia-related neurodevelopmental rat models appear to be brain region and animal model dependent. The results of this study support previous findings suggesting abnormal complex I expression as a pathological characteristic of schizophrenia rather than an effect of medication.

The expression of genes involved in glucose metabolism is affected by N‐methyl‐D‐aspartate receptor antagonism: A putative link between metabolism and an animal model of psychosis

“…Mitochondrial dysfunctions have been demonstrated to lead to the generation of reactive oxygen species or to induce apoptosis mechanisms, which may sustain neurotoxic damage and have been implicated in schizophrenia pathophysiology (Ben‐Shachar,2002; Rezin et al,2009). Increased activity and protein expression of mitochondrial complex I have been found in schizophrenics and in an animal model of schizophrenia (Ben‐Shachar et al,2009; Rosenfeld et al,2011), and a correlation between increased mitochondrial complex I activity in platelets and increased glucose uptake in brain has been described for schizophrenic subjects showing prominent positive symptoms (Ben‐Shachar et al,2007). Increased mitochondrial complex I activity and oxidative damage have been found in selected rat brain areas after subchronic or acute administration of subanesthetic doses of ketamine, respectively (de Oliveira et al,2009, 2011).…”

Mitochondrial complex I and III gene mRNA levels in schizophrenia, and their relationship with clinical features

“…Some studies that examined brain tissue in schizophrenia patients reported an increase in activation of the mitochondrial complex, as compared to controls [ 6 , 7 ], whereas others reported a decrease [ 8 , 9 ]. Location and function of the brain tissue examined were important in the formation of these results.…”

Gene expression dynamics following mithramycin treatment: A possible model for post‐chemotherapy cognitive impairment

“…In line with the latter, a similar age‐dependent dynamic of complex I subunits protein levels (NDUFV1, NDUFV2 and NDUFS1) in the PFC of early in life lesion and non‐lesion rats was reported. Thus, prepubertal ventral hippocampus lesions, which resulted in a schizophrenia‐like behavioural phenotype, suppressed age‐dependent increases in these protein . The inverse tendency in the expression of genes in the MTR treated rats, was not a global rearrangement of the whole transcriptome, but was rather specific.…”