A sensitive period of mice inhibitory system to neonatal GABA enhancement by vigabatrin is brain region dependent.
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.
Levav-Rabkin
Tamar
T
Faculty of Health Sciences, Department of Developmental Molecular Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Melamed
Osnat
O
Clarke
Gerard
G
Farber
Malca
M
Cryan
John F
JF
Dinan
Timothy G
TG
Grossman
Yoram
Y
Golan
Hava M
HM
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
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