Genetic predisposition and early life experience interact to determine glutamate transporter (GLT1) and solute carrier family 12 member 5 (KCC2) levels in rat hippocampus

作者：Sterley Toni Lee^*; Howells Fleur M; Dimatelis Jacqueline J; Russell Vivienne A

来源：Metabolic Brain Disease, 2016, 31(1): 169-182.

DOI：10.1007/s11011-015-9742-5

• Spontaneously hypertensive rat (SHR)
• Wistar-Kyoto rat (WKY)
• Attention-deficit/hyperactivity disorder (ADHD)
• Maternal separation
• Proteomics
• Hippocampus
• KCC2
• GLT1

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders. While it is typically treated with medications that target dopamine and norepinephrine transmission, there is increasing evidence that other neurotransmitter systems, such as glutamate and GABA, may be involved. The aetiology of ADHD is unknown; however, there is evidence that early life stress may contribute to the development of the disorder. In the present study we used proteomic analysis (iTRAQ) followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis to investigate hippocampal protein profiles of three rat strains: an animal model of ADHD, spontaneously hypertensive rats (SHR), their control Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD). We additionally investigated how these protein profiles are affected by maternal separation, a model of early life stress. Our findings show that solute carrier family 12 member 5 (KCC2) is increased in SHR hippocampus. The glutamate transporter GLT1 splice variant, GLT1b, was increased (proteomic analysis) while total GLT1 (comprised mostly of GLT1a splice variant) was reduced (Western blot analysis) in SHR hippocampus, compared to WKY and SD - a pattern that is consistent with elevated extracellular glutamate levels. Maternal separation increased total GLT1 in hippocampi of SHR, WKY, and SD, and reduced GLT1b in SHR hippocampus. Together these findings provide evidence for disturbed glutamatergic and GABAergic transmission in SHR hippocampus, maternal separation effects on glutamate uptake in hippocampi of all three strains, as well a unique effect of maternal separation on GLT1b levels in SHR hippocampus. These data suggest significant involvement of glutamatergic and GABAergic transmission in the neuropathophysiology of ADHD, and implicates changes in glutamatergic transmission as a result of early life stress.

• 出版日期2016-2