Overexpression of gamma-aminobutyric acid transporter subtype I leads to cognitive deterioration in transgenic mice.
OBJECTIVE
To explore the physiological role of gamma-aminobutyric acid transporter subtype I (GAT1) in cognition.


METHODS
Transgenic mice were produced by pronuclei microinjection method. Integration of transgene was identified by Southern-blot and PCR analysis in various generations. Level of GAT1 mRNA in a variety of tissues was evaluated by semi-quantitative RT-PCR analysis. GAT1 protein was detected by immunofluorescence and histochemistry analysis. Associative learning capacity was analyzed by conditioned avoidance task. Memory retention was assessed by novel object recognition test. Morphology of synaptosomes was examined by electron microscope.


RESULTS
Four independent founder mice bearing various copies of transgene were generated. GAT1 was evidently overexpressed at both mRNA and protein level in a variety of tissues from transgenic mice. In comparison with wild-type mice, transgenic mice exhibited significantly declined associative learning capacity (P < 0.01) and decreased memory retention (P < 0.01 in 1-h-retention, and P < 0.05 in 1-d-retention). In addition, the amount of asymmetric synapses in the brain of transgenic mice was reduced approximately by 24 %, relative to wild-type mice.


CONCLUSIONS
Overexpression of GAT1 in mice results in cognitive deterioration, indicating that the alteration in the expression of gamma-aminobutyric acid transporters is involved in the pathophysiological mechanism underlying some cognitive deficiencies.
Ma
Y H
YH
Shanghai Institute of Physiology, Chinese Academy of Sciences, Shanghai 200031, China.
Zhou
X G
XG
Duan
S H
SH
Hu
J H
JH
Lu
B F
BF
Yu
Y
Y
Mei
Z T
ZT
Fei
J
J
Guo
L H
LH
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002352:Carrier Proteins / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics; D003072:Cognition Disorders / Q000139:chemically induced*; D050485:GABA Plasma Membrane Transport Proteins; D015870:Gene Expression; D008565:Membrane Proteins / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027361:Organic Anion Transporters; D012333:RNA, Messenger / Q000096:biosynthesis; D012153:Retention, Psychology / Q000187:drug effects; D013574:Synaptosomes / Q000473:pathology
D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C493414:Slc6a1 protein, mouse