Long-term effects on the developing brain through a brief alteration of NMDA or GABAA receptor mediated neurotransmission

Neurotransmitter signaling is essential for physiologic brain development. Sedative and anticonvulsant agents that reduce neuronal excitability via antagonism at N-methyl-D-aspartate receptors (NMDARs) and/or agonism at gamma-aminobutyric acid subtype A receptors (GABAARs) are applied frequently in obstetric and pediatric medicine. Such drugs have the potential to induce widespread apoptotic neurodegeneration in the developing rodent brain as an acute effect. We now demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABAAR agonist phenobarbital has not only acute but also long-term effects on the developing brain. We detected changes of the brain proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6. These findings suggest that a suppression of synaptic neurotransmission during brain development triggers not only apoptosis, oxidative stress, and inflammation, but has also an effect on cell proliferation and neuronal circuit formation. Histological evaluations of the brains revealed decreased cell proliferation and are thus consistent with brain protein changes. These effects appear to be age-dependent as protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Our results point toward several pathways modulated by a reduction of neuronal excitability that might interfere with critical developmental events and thus affirm concerns about the impact of NMDAR- and/or GABAAR-modulating drugs on human brain development.