PMC

During normoxia the TCA cycle has many reversible reactions with 2 “stop/go” points of irreversible reactions, at the conversion of oxaloacetate to citrate and likewise the conversion of α-ketoglutarate to succinyl CoA. During hypoxia, as the cell needs ATP and NAD+, the TCA metabolite flow predominately proceeds towards succinate production from α-ketoglutarate to account for ATP lost from electron transport failure and oxaloacetate is preferentially converted to malate to increase mitochondrial NAD. This leads to a build-up of fumarate and succinate which are known to inhibit the function of the α-ketoglutarate dependent dioxygenases. It has also been shown that under hypoxic conditions α-ketoglutarate can be converted, primarily by lactate dehydrogenase, to L-hydroxyglutarate, which also can inhibit members of the α-ketoglutarate dependent dioxygenase family. The metabolites which have been shown to either directly promote (α-ketoglutarate) or inhibit (succinate, fumarate and L-hydroxyglutarate) activity of the α-ketoglutarate dependent dioxygenases are highlighted in bold.

During PTB related insults, glia within the CNS are particularly vulnerable to stressors and mediate many of the pathogenic outcomes associated with PTB. Astrocytes are central to the excitotoxic response, which involves glutamate recycling and its de novo synthesis. Oligodendrocytes and oligodendrocyte precursor cells (OPC) are vulnerable to oxidative stress and other factors associated with hypoxia, inflammation and excitotoxicity as periods critical for their correct maturation and development overlap with the time during which PTB related insults may occur [, ] (surface area of an individual OPC’s membrane can increase up to 6,500 fold during these times []). The death of OPCs is of particular importance during development as this leads to a shortage of mature oligodendrocytes which may result in aberrant myelination in deep white matter tracts of the brain, leading to impaired signalling and neuronal death, which can be seen pathologically as periventricular leukomalacia, an anatomical feature of cerebral palsy. Microglia can become activated in response to infection in utero or postnatally, this population transition is central to the inflammatory response within the CNS and increased levels of microglial activation can also be seen in post-mortem ASD tissue in the prefrontal cortex of male patients [].