Abstract
Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(−/−) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
Highlights
The activation of N-methyl-D-aspartate (NMDA) receptors has been implicated in many aspects of brain development in the early embryo
There were no significant differences between any of the data points in the stimulus–response relationship between slices prepared from control animals and those from animals born to dams treated with kynurenine and probenecid (Fig. 1A)
The changes in the ratio of fEPSPs (Fig. 1C) or population spike amplitudes (Fig. 1D) at different interpulse intervals were very similar between slices taken from controls and animals exposed to kynurenine and probenecid, with no significant differences between the groups
Summary
The activation of N-methyl-D-aspartate (NMDA) receptors has been implicated in many aspects of brain development in the early embryo. These and other aspects of neuronal and synaptic development determine synaptic function and plasticity in the mature, postnatal, offspring (Iwasato et al, 2000; Myers et al, 2000; Ramoa et al, 2001; Fagiolini et al, 2003) Their importance is reflected in the loss of neurons and synapses following treatment of animals with NMDA receptor blocking agents (Ikonomidou et al, 1999; Dikranian et al, 2001; Harris et al, 2003; Vincent et al, 2004), which can result in significant central abnormalities of structure and behavior comparable with those seen in schizophrenia and other CNS disorders (Cochran et al, 2003; Harris et al, 2003; du Bois and Huang, 2007; Stone and Darlington, 2013).
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