Peer-Reviewed Journal Details
Mandatory Fields
Levav-Rabkin, T; Melamed, O; Clarke, G; Farber, M; Cryan, JF; Dinan, TG; Grossman, Y; Golan, HM;
2010
January
Neuropsychopharmacology
A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent
Validated
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Optional Fields
hippocampus glutamate decarboxylase NKCC1 KCC2 calbindin parvalbumin GLUTAMIC-ACID DECARBOXYLASE CATION-CHLORIDE COTRANSPORTERS THALAMIC RETICULAR NUCLEUS SUBUNIT MESSENGER-RNAS RAT CEREBRAL-CORTEX SYNAPTIC VESICLES NEURODEVELOPMENTAL DISORDERS MYOINOSITOL MONOPHOSPHATASE HIPPOCAMPAL-FORMATION POSTNATAL-DEVELOPMENT
35
1138
1154
Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1-7 and P4-14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl- co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4-14 hippocampi and cerebral cortices. Analysis of the Ca2+ binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4-14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4-14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs. Neuropsychopharmacology (2010) 35, 1138-1154; doi: 10.1038/npp.2009.219; published online 30 December 2009
DOI 10.1038/npp.2009.219
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