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Highlights-An inhibitor of kynurenine-3-monoxygenase was administered to pregnant female rats-Adult offspring at postnatal day 60 (P60) showed alterations in synaptic plasticity-Expression of GluN2A, sonic hedgehog and other developmental proteins were changed-Most earlier protein changes had disappeared with no changes in RNA or learning tasks-Prenatal kynurenine pathway inhibition produces persistent synaptic and protein changes 3 Abstract During early brain development, NMDA receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanised and the brains removed for examination. Analysis of protein expression by western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using qRT-PCR. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.

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A multifocal damage of the testis was obtained when rats were injected intravenously or under the tunica albuginea of the testis with a rabbit antiseminiferous tubule basement membrane serum. The damage was characterized by foci of perivascular and peritubular infiltrates of mononuclear round cells, infolding, thickening, and rupture of the seminiferous tubular wall and different degrees of injury of the germinal epithelium such as, cell disorganization, cell sloughing, and atrophy. Delamination and thickening of seminiferous tubule basement membrane and vacuolization of the Sertoli cell cytoplasm was often observed by electron microscopy. A linear deposit of rabbit gamma-globulin was detected by immunohistochemical techniques along the basement membranes of the seminiferous tubules and vessels. Testicular damage was not detected in rats injected with normal rabbit serum, used as control. In the kidneys of rats injected intravenously with the immune serum, a deposit of rabbit gamma-globulin was detected along glomerular basement membrane. Focal areas of mononuclear cell infiltrates, hypercellularity of glomeruli and thickening of glomerular capillary walls and Bowman's capsule were also observed.