Alteration of Mitochondrial Morphology and Function in Juvenile Rats Exposed to Maternal Immune Activation

Background: Maternal infection is a profound risk factor for neuropsychiatric disorders, including autism, schizophrenia and bipolar disorder. Studies on animal models indicate that maternal immune activation (MIA) may lead to neurochemical and behavioral abnormalities in the offspring. Additionally, mitochondrial dysfunction has been proposed as a major consequence of MIA, and may represent a critical link between neuronal dysfunction and behavioral phenotypes observed in the adult offspring.

Objectives: Here, we analyze the effect of MIA on the morphological abnormalities and alteration of mitochondrial function in rat offspring.

Methods: MIA was evoked by single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) (100 μg/kg) to pregnant rats at embryonic day 9.5. Hippocampus and brain cortex of juvenile (on 52-53 post-natal day) male rat offspring were analyzed. Molecular biology, biochemistry and transmission electron microscopy were used in the research

Results: We demonstrated that MIA evoked changes in brain morphology, especially in ultrastructure of mitochondria: we observed fragmented cristae with evidence of an expanded matrix compartment or disrupted membrane in both cerebral cortex and hippocampus of juvenile rat offspring. These alterations were accompanied by reduced mitochondrial membrane potentials and enhanced oxidative stress, measured by glutathione levels. The data presented changes in expression of electron transport chain (ETC) complexes. In the cerebral cortex of MIA rats the expression of complex I subunit (mt-Nd1), complex III subunit (mt-Cyb) and complex IV subunit (mt-Co1) was decreased, however in hippocampus only mt-Co1 was reduced. We also demonstrated that MIA altered transcription of proteins regulating mitochondrial fusion-fission. The reduced level of mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), with concomitant elevation of dynamin related protein 1 (Drp1) was observed in the cortex, whereas the mitochondrial fission 1 (Fis1) expression was altered only in hippocampus of MIA rats. Moreover, we showed down-regulation of transcription factors responsible for mitochondrial biogenesis: Pgc1α (Ppargc) in cerebral cortex and Tfam in both cerebral cortex and hippocampus of juvenile MIA offspring were reduced.

Conclusions: The observed changes in mitochondrial ultrastructure, function and gene expression of main proteins regulating mitochondrial dynamics/biogenesis and ETC subunits may help in understanding their role in synaptic stress. These findings may contribute to a potential point for novel therapeutic strategies for inflammation-related pathology in neurodevelopmental and neuropsychiatric disorders through the protection of synaptic transmission by targeting mitochondrial deficits. Future work will need to explore associations with behaviors, the impact of interventions, and the correlates in clinical populations.

Supported by the NCN Grant (2016/23/D/NZ4/03572)