Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity

Jessica L. Bolton; Anton Schulmann; Megan M. Garcia-Curran; Limor Regev; Yuncai Chen; Noriko Kamei; Manlin Shao; Akanksha Singh-Taylor; Shan Jiang; Yoav Noam; Jenny Molet; Ali Mortazavi; Tallie Z. Baram

Cell Reports (Dec 2020)

Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity

Jessica L. Bolton,
Anton Schulmann,
Megan M. Garcia-Curran,
Limor Regev,
Yuncai Chen,
Noriko Kamei,
Manlin Shao,
Akanksha Singh-Taylor,
Shan Jiang,
Yoav Noam,
Jenny Molet,
Ali Mortazavi,
Tallie Z. Baram

Affiliations

Jessica L. Bolton: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Anton Schulmann: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Megan M. Garcia-Curran: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Limor Regev: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Yuncai Chen: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Noriko Kamei: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Manlin Shao: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Akanksha Singh-Taylor: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Shan Jiang: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-4475, USA
Yoav Noam: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Jenny Molet: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
Ali Mortazavi: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-4475, USA
Tallie Z. Baram: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92697-4475, USA; Corresponding author

Journal volume & issue: Vol. 33, no. 11
p. 108511

Abstract

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Summary: Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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