title: Subcortical glutamate mediates the reduction of short-range functional connectivity with age in a developmental cohort.
abstract: Marked changes in brain physiology and structure take place between childhood and adulthood, including changes in functional connectivity and changes in the balance between main excitatory and inhibitory neurotransmitters glutamate (Glu) and GABA. The balance of these neurotransmitters is thought to underlie neural activity in general and functional connectivity networks in particular, but so far no studies have investigated the relationship between human development related differences in these neurotransmitters and concomitant changes in functional connectivity. GABA+/H2O and Glu/H2O levels were acquired in a group of healthy children, adolescents, and adults in a subcortical (basal ganglia) region, as well as in a frontal region in adolescents and adults. Our results showed higher GABA+/Glu with age in both the subcortical and the frontal voxel, which were differentially associated with significantly lower Glu/H2O with age in the subcortical voxel and by significantly higher GABA+/H2O with age in the frontal voxel. Using a seed-to-voxel analysis, we were further able to show that functional connectivity between the putamen (seed) and other subcortical structures was lower with age. Lower subcortical Glu/H2O with age mediated the lower connectivity in the dorsal putamen. Based on these results, and the potential role of Glu in synaptic pruning, we suggest that lower Glu mediates a reduction of local connectivity during human development.
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Carmen
authors.identifier: http://orcid.org/0000-0003-2989-3263
authors.initials: C
authors.lastname: Ghisleni
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Steffen
authors.identifier: http://orcid.org/0000-0002-2909-0906
authors.initials: S
authors.lastname: Bollmann
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland.
authors.forename: Simon-Shlomo
authors.identifier: http://orcid.org/0000-0002-9457-9177
authors.initials: SS
authors.lastname: Poil
authors.affiliation: Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland, Department of Child and Adolescent Psychiatry, University of Zurich, 8032 Zurich, Switzerland, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, 68159 Mannheim, Germany, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brandeis
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Ernst
authors.initials: E
authors.lastname: Martin
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Neuroradiology Clinic, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Lars
authors.identifier: http://orcid.org/0000-0002-3750-1100
authors.initials: L
authors.lastname: Michels
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland.
authors.forename: Ruth L
authors.identifier: http://orcid.org/0000-0001-5932-7786
authors.initials: RL
authors.lastname: O'Gorman
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland, Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zürich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland, Department of Psychology, University of Zurich, 8050 Zurich, Switzerland, p.klaver@psychologie.uzh.ch.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-6541-9975
authors.initials: P
authors.lastname: Klaver
mesh_terms: D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001479:Basal Ganglia / Q000098:blood supply / Q000254:growth & development* / Q000378:metabolism*; D001931:Brain Mapping; D002648:Child; D015331:Cohort Studies; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D018709:Statistics, Nonparametric; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C000179:N-acetylaspartate; D010100:Oxygen
keywords: GABA; development; functional connectivity; glutamate; magnetic resonance spectroscopy; working memory