Brief alteration of NMDA or GABAA receptor-mediated neurotransmission has long term effects on the developing cerebral cortex.
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 (GABA(A)Rs) are applied frequently in obstetric and pediatric medicine. We demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABA(A)R agonist phenobarbital not only has acute but also long term effects on the cerebral cortex. Changes of the cerebral cortex proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6 suggest that a suppression of synaptic neurotransmission during brain development dysregulates proteins associated with apoptosis, oxidative stress, inflammation, cell proliferation, and neuronal circuit formation. These effects appear to be age-dependent as most protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Previously performed histological evaluations of the brains revealed widespread apoptosis and decreased cell proliferation following such a drug treatment in infancy and are thus consistent with brain protein changes reported in this study. 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 GABA(A)R-modulating drugs on human brain development.
Kaindl
Angela M
AM
Department of Pediatric Neurology, Institute of Human Genetics, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. angela.kaindl@charite.de
Koppelstaetter
Andrea
A
Nebrich
Grit
G
Stuwe
Janine
J
Sifringer
Marco
M
Zabel
Claus
C
Klose
Joachim
J
Ikonomidou
Chrysanthy
C
D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D058785:GABA-A Receptor Agonists; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D020543:Proteome / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D058785:GABA-A Receptor Agonists; D020543:Proteome; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010634:Phenobarbital