Long-lasting glutamatergic modulation induced by neonatal GABA enhancement in mice.
A subgroup of anticonvulsant and neuroleptic drugs acts through the potentiation of GABA pathways. The regulatory role of GABA in neuronal circuit formation is related to its depolarizing action that supports activity-dependent synaptogenesis. We hypothesized that elevated levels of GABA in the immature brain modify synaptogenesis in excitatory synapses and consequently affect mice behavior. In support of this theory, we showed previously that neonatal exposure to a GABA-transaminase inhibitor (Vigabatrin, GVG) modifies the expression of presynaptic proteins and suppresses excitatory synaptic potentials. To further characterize this phenomenon, we examined the effect of GVG applied during postnatal days 4-14, during the switch in GABA function from a depolarizing to a hyperpolarizing substance, on the development of excitatory synapses and mice sociability. Early exposure to GVG induced differential effects on synaptic proteins in the hippocampus and the cerebral cortex, including the downregulation of GluR1/GluR2 and NR2A/NR2B ratios in the hippocampus cytoplasm, a minute effect on the regulatory proteins CAMKII and PKA in the cerebral cortex, and increases in pGluR1, CAMKII, PKA and Reelin levels. Early GVG exposure was also associated with region specific regulation of monoamines, reduction in hippocampal DA, and enhancement of cortical NE levels. Age-dependent modified sociability and lack of preference for social interactions were observed in mice treated with GVG. Overall, early life exposure to GVG is expected to alter cortico-hippocampal axis connectivity and balance due to the different effects GVG has on key synaptic proteins in the associated brain regions, thus potentially causing behavioral impairment.
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Osnat
O
Melamed
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Tamar
T
Levav-Rabkin
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Chava
C
Zukerman
Department of Psychiatry, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Gerard
G
Clarke
Department of Anatomy & Neuroscience, University College Cork, Ireland.
John F
JF
Cryan
Department of Psychiatry, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Timothy G
TG
Dinan
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Yoram
Y
Grossman
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: havag@bgu.ac.il.
Hava M
HM
Golan
D000818:Animals; D000831:Animals, Newborn; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D018682:GABA Agents / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D012919:Social Behavior; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015816:Cell Adhesion Molecules, Neuronal; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine; D016326:Extracellular Matrix Proteins; D018682:GABA Agents; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C000717128:Reln protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2
GluR1; Monoamine; Reelin; Social behavior