Prenatal metformin exposure or organic cation transporter 3 knock-out curbs social interaction preference in male mice.

Poorly managed gestational diabetes can lead to severe complications for mother and child including fetal overgrowth, neonatal hypoglycemia and increased autism risk. Use of metformin to control it is relatively new and promising. Yet safety concerns regarding gestational metformin use remain, as its long-term effects in offspring are unclear. In light of beneficial findings with metformin for adult mouse social behavior, we hypothesized gestational metformin treatment might also promote offspring sociability. To test this, metformin was administered to non-diabetic, lean C57BL/6 J female mice at mating, with treatment discontinued at birth or wean. Male offspring exposed to metformin through birth lost social interaction preference relative to controls by time in chambers, but not by sniffing measures. Further, prenatal metformin exposure appeared to enhance social novelty preference only in females. However due to unbalanced litters and lack of statistical power, firm establishment of any sex-dependency of metformin's effects on sociability was not possible. Since organic cation transporter 3 (OCT3) transports metformin and is dense in placenta, social preferences of OCT3 knock-out males were measured. Relative to wild-type, OCT3 knock-outs had reduced interaction preference. Our data indicate gestational metformin exposure under non-diabetic conditions, or lack of OCT3, can impair social behavior in male C57BL6/J mice. Since OCT3 transports serotonin and tryptophan, impaired placental OCT3 function is one common mechanism that could persistently impact central serotonin systems and social behavior. Yet no gross alterations in serotonergic function were evident by measure of serotonin transporter density in OCT3, or serotonin turnover in metformin-exposed offspring brains. Mechanisms underlying the behavioral outcomes, and if with gestational diabetes the same would occur, remain unclear. Metformin's impacts on placental transporters and serotonin metabolism or AMPK activity in fetal brain need further investigation to clarify benefits and risks to offspring sociability from use of metformin to treat gestational diabetes.

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