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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number147254
JournalBrain research
Volume1754
DOIs
StatePublished - Mar 1 2021

Keywords

  • BDNF
  • Behavior
  • DNA methylation
  • Development
  • Nuclear size
  • Schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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