Hippocampal Transcriptome Profile of Persistent Memory Rescue in a Mouse Model of THRA1 Mutation-Mediated Resistance to Thyroid Hormone

Sci Rep. 2016 Jan 8;6:18617. doi: 10.1038/srep18617.

Abstract

Hypothyroidism due to THRA1 (gene coding for thyroid hormone receptor α1) mutation-mediated Resistance to Thyroid Hormone (RTH) has been recently reported in human and is associated with memory deficits similar to those found in a mouse model for Thra1 mutation mediated RTH (Thra1(+/m) mice). Here, we show that a short-term treatment of Thra1(+/m) mice with GABAA receptor antagonist pentylenetetrazol (PTZ) completely and durably rescues their memory performance. In the CA1 region of the hippocampus, improvement of memory is associated with increased in long-term potentiation (LTP) and an augmentation of density of dendritic spines (DDS) onto the apical dendrites of pyramidal cells reflecting an increase in the local excitatory drive. Unbiased gene profiling analysis of hippocampi of treated Thra1(+/+) and Thra1(+/m) mice were performed two weeks and three months post treatment and identified co-expression modules that include differentially expressed genes related with and predicting higher memory, LTP and DDS in the hippocampi of PTZ-treated animals. We observed that PTZ treatment changed similar sets of genes in both Thra1(+/+) and Thra1(+/m) mice, which are known to be involved in memory consolidation and neurotransmission dynamics and could participate in the persistent effects of PTZ on memory recovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / pathology
  • Dendritic Spines / drug effects
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects
  • GABA-A Receptor Antagonists / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Hypothyroidism / complications
  • Hypothyroidism / drug therapy*
  • Hypothyroidism / genetics
  • Hypothyroidism / metabolism
  • Long-Term Potentiation / drug effects
  • Male
  • Memory Disorders / complications
  • Memory Disorders / drug therapy*
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pentylenetetrazole / pharmacology*
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Synaptic Transmission / drug effects
  • Thyroid Hormone Receptors alpha / deficiency
  • Thyroid Hormone Receptors alpha / genetics*
  • Thyroid Hormones / genetics*
  • Thyroid Hormones / metabolism
  • Transcriptome*

Substances

  • GABA-A Receptor Antagonists
  • Nerve Tissue Proteins
  • Thyroid Hormone Receptors alpha
  • Thyroid Hormones
  • Pentylenetetrazole