Indispensability of the glutamate transporters GLAST and GLT1 to brain development

doi:10.1073/pnas.0509144103

Indispensability of the glutamate transporters GLAST and GLT1 to brain development

*Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
^†Laboratory for Neural Architecture,
^‡Brain Development Research Group,
^‖Laboratory for Cell Culture Development, and
**Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan;
^¶Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and
^‡‡Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan

Edited by Michael V. L. Bennett, Albert Einstein College of Medicine, Bronx, NY, and approved June 22, 2006 (received for review October 19, 2005)

Abstract

Previous in vitro studies have shown that the neurotransmitter glutamate is important in brain development. Paradoxically, loss-of-function mouse models of glutamatergic signaling that are generated by genetic deletion of glutamate receptors or glutamate release show normal brain assembly. We examined the direct consequences on brain development of extracellular glutamate buildup due to the depletion of the glutamate transporters GLAST and GLT1. GLAST/GLT1 double knockout mice show multiple brain defects, including cortical, hippocampal, and olfactory bulb disorganization with perinatal mortality. Here, we report abnormal formation of the neocortex in GLAST/GLT1 mutants. Several essential aspects of neuronal development, such as stem cell proliferation, radial migration, neuronal differentiation, and survival of SP neurons, were impaired. These results provide direct in vivo evidence that GLAST and GLT1 are necessary for brain development through regulation of extracellular glutamate concentration and show that an important mechanism is likely to be maintenance of glutamate-mediated synaptic transmission.

Footnotes

^††To whom correspondence may be addressed. E-mail: tom{at}brain.riken.jp or tanaka.aud{at}mri.tmd.ac.jp
↵ ^§Present address: Cellular and Molecular Toxicology Division, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagayaku, Tokyo 158-8501, Japan.
Author contributions: T.R.M., K. Tanemura, T.H., and K. Tanaka designed research; T.R.M., K. Tanemura, M.M., K.Y., K.O., M.W., and K. Tanaka performed research; T.R.M., K. Tanemura, R.N., M.O., K.O., and M.W. contributed new reagents/analytic tools; T.R.M., K. Tanemura, M.M., R.N., K.Y., T.K., M.O., K.O., M.W., and T.H. analyzed data; and T.R.M. and K. Tanaka wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

En,

embryonic day n;

PCNA,

proliferating cell nuclear antigen;

MAP2,

microtubule-associated protein 2;

CT,

corticothalamic;

TC,

thalamocortical;

DiI,

1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine;

AMPA,

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;

VZ,

ventricular zone;

CP,

cortical plate;

SP,

subplate.
Freely available online through the PNAS open access option.