Bdnf deficiency in the neonatal hippocampus contributes to global dna hypomethylation and adult behavioral changes

Daniel A Paredes; Ahmad Jalloh; Briony J Catlow; Amritha Jaishankar; Seungmae Seo; Dennisse V Jimenez; Keri Martinowich; Marcelo Diaz-Bustamante; Daniel J Hoeppner; Ronald D G McKay

doi:10.1016/j.brainres.2020.147254

Bdnf deficiency in the neonatal hippocampus contributes to global dna hypomethylation and adult behavioral changes

Brain Res. 2021 Mar 1:1754:147254. doi: 10.1016/j.brainres.2020.147254. Epub 2021 Jan 7.

Authors

Affiliations

¹ Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. Electronic address: Daniel.paredes@du.edu.
² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
³ Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
⁴ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
⁵ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Pediatrics, Columbia University, New York, NY, USA.
⁶ Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, USA.
⁷ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Physiology, Johns Hopkins University, Baltimore, MD, USA.

PMID: 33422542
DOI: 10.1016/j.brainres.2020.147254

Abstract

Schizophrenia is a neurodevelopmental psychiatric disorder, encompassing genetic and environmental risk factors. For several decades, investigators have been implementing the use of lesions of the neonatal rodent hippocampus to model schizophrenia, resulting in a broad spectrum of adult schizophrenia-related behavioral changes. Despite the extensive use of these proposed animal models of schizophrenia, the mechanisms by which these lesions result in schizophrenia-like behavioral alterations remain unclear. Here we provide in vivo evidence that transient pharmacological inactivation of the hippocampus via tetrodotoxin microinjections or a genetic reduction in brain derived neurotrophic factor (BDNF) protein levels (BDNF^+/- rats) lead to global DNA hypomethylation, disrupted maturation of the neuronal nucleus and aberrant acoustic startle response in the adult rat. The similarity between the effects of the two treatments strongly indicate that BDNF signaling is involved in effects obtained after the TTX microinjections. These findings may shed light on the cellular mechanisms underlying the phenotypical features of neonatal transient inhibition of the hippocampus as a preclinical model of schizophrenia and suggest that BDNF signaling represents a target pathway for development of novel treatment therapies.

Keywords: BDNF; Behavior; DNA methylation; Development; Nuclear size; Schizophrenia.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Animals, Newborn
Behavior, Animal / physiology*
Brain-Derived Neurotrophic Factor / deficiency*
Brain-Derived Neurotrophic Factor / metabolism
DNA / metabolism*
DNA Methylation / physiology*
Hippocampus / metabolism*
Neurons / metabolism
Rats
Reflex, Startle / genetics
Reflex, Startle / physiology
Schizophrenia / genetics
Schizophrenia / metabolism

Substances

Brain-Derived Neurotrophic Factor
DNA