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Atrophy of pyramidal neurons and increased stress-induced glutamate levels in CA3 following chronic suppression of adult neurogenesis

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Abstract

Following their birth in the adult hippocampal dentate gyrus, newborn progenitor cells migrate into the granule cell layer where they differentiate, mature, and functionally integrate into existing circuitry. The hypothesis that adult hippocampal neurogenesis is physiologically important has gained traction, but the precise role of newborn neurons in hippocampal function remains unclear. We investigated whether loss of new neurons impacts dendrite morphology and glutamate levels in area CA3 of the hippocampus by utilizing a human GFAP promoter-driven thymidine kinase genetic mouse model to conditionally suppress adult neurogenesis. We found that chronic ablation of new neurons induces remodeling in CA3 pyramidal cells and increases stress-induced release of the neurotransmitter glutamate. The ability of persistent impairment of adult neurogenesis to influence hippocampal dendrite morphology and excitatory amino acid neurotransmission has important implications for elucidating newborn neuron function, and in particular, understanding the role of these cells in stress-related excitoxicity.

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Acknowledgments

This work was funded by the National Institute of Mental Health Intramural Research Program and the Lieber Institute for Brain Development. RJS and KM were supported in part by NARSAD Young Investigator Awards.

Conflict of interest

The authors declare that they have no conflict of interest. HKM is a paid employee of Janssen Research & Development.

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Authors and Affiliations

  1. Mood and Anxiety Disorders Program, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, 20892, USA

    Robert J. Schloesser, Dennisse V. Jimenez, Husseini K. Manji & Keri Martinowich

  2. Genes, Cognition and Psychosis Program, NIMH, NIH, Bethesda, MD, 20892, USA

    Nicholas F. Hardy & Keri Martinowich

  3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N. Wolfe Street , #347B, Baltimore, MD , 21205, USA

    Robert J. Schloesser, Dennisse V. Jimenez, Nicholas F. Hardy, Daniel Paredes, Briony J. Catlow, Ronald D. McKay & Keri Martinowich

  4. Janssen Research & Development, Titusville, NJ, USA

    Husseini K. Manji

  5. Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke (NINDS), NIH, Bethesda, MD, 20892, USA

    Daniel Paredes, Briony J. Catlow & Ronald D. McKay

  6. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Robert J. Schloesser

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  1. Robert J. Schloesser
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  2. Dennisse V. Jimenez
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  6. Husseini K. Manji
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  8. Keri Martinowich
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Correspondence to Keri Martinowich.

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Schloesser, R.J., Jimenez, D.V., Hardy, N.F. et al. Atrophy of pyramidal neurons and increased stress-induced glutamate levels in CA3 following chronic suppression of adult neurogenesis. Brain Struct Funct 219, 1139–1148 (2014). https://doi.org/10.1007/s00429-013-0532-8

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