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

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Abstract

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.

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Abbreviations

P:

postnatal day

SHR:

spontaneously hypertensive rat

WKY:

Wistar-Kyoto rat

SD:

Sprague-Dawley rat

KCC2:

solute carrier family 12 member 5

iTRAQ:

isobaric tag for relative and absolute quantitation

SDS-PAGE:

sodium dodecyl sulfate polyacrylamide gel electrophoresis

MALDI:

matrix-assisted laser desorption/ionization

MS/MS:

tandem mass spectrometry

ADHD:

attention-deficit/hyperactivity disorder

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Acknowledgments

We thank the Faculty of Health Sciences Research Committee (FRC) of the University of Cape Town for the Postgraduate Publication Incentive Award, as well as the University of Cape Town and the National Research Foundation (NRF) for their continued support. We also thank Dr. Mare Vlok of the Centre for Proteomic and Genomic Research (CPGR) for performing the proteomic analysis of the samples in the present study. Thank you also to Nuraan Ismail and Abdul Karriem Samuels who cared for the animals. Any opinion, finding and conclusion or recommendation expressed in this material is that of the authors and the NRF does not accept any liability in this regard.

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  1. Toni-Lee Sterley

    Present address: University of Calgary, Hotchkiss Brain Institute, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada

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  1. Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Toni-Lee Sterley, Jacqueline J. Dimatelis & Vivienne A. Russell

  2. Department of Psychiatry, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Fleur M. Howells

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The research involved the use of animals. All applicable international, national and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Cape Town.

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This study was funded by the National Research Foundation (NRF).

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Sterley, TL., Howells, F.M., Dimatelis, J.J. et al. Genetic predisposition and early life experience interact to determine glutamate transporter (GLT1) and solute carrier family 12 member 5 (KCC2) levels in rat hippocampus. Metab Brain Dis 31, 169–182 (2016). https://doi.org/10.1007/s11011-015-9742-5

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