title: A sensitive period of mice inhibitory system to neonatal GABA enhancement by vigabatrin is brain region dependent.
abstract: 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 Ca(2+) 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.
authors.affiliation: Faculty of Health Sciences, Department of Developmental Molecular Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Levav-Rabkin
authors.forename: Osnat
authors.initials: O
authors.lastname: Melamed
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.forename: Malca
authors.initials: M
authors.lastname: Farber
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: Yoram
authors.initials: Y
authors.lastname: Grossman
authors.forename: Hava M
authors.initials: HM
authors.lastname: Golan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002452:Cell Count; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018682:GABA Agents / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010320:Parvalbumins / Q000378:metabolism; D011897:Random Allocation; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D020888:Vigabatrin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D064026:Calbindins; D018682:GABA Agents; D005968:Glutamate Decarboxylase; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse; C492244:Viaat protein, mouse; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2