cubes

Abstract

Integrative behavioral, molecular and electrophysiological analyses of female Mecp2tm1.1 Bird Rett Syndrome model

J. S-PADILLA1 J. PALMA1, S. GELMAN1, K. KRETSCHMANNOVA1, J. BELTRAN1, M. KWAN1, L. THIEDE1, T. HANANIA1, A. GHAVAMI1
1PsychoGenics, Inc., Paramus, NJ, USA

Rett Syndrome is a neurodevelopmental disorder caused by mutations in the Mecp2 gene encoding for the methyl-CpG-binding protein 2 (MeCP2). While most studies have analyzed male Mecp2 mice, analysis of female mice is clinically relevant to the female population of Rett syndrome patients. A combination of behavioral, molecular, and electrophysiological techniques has been employed here in the female Mecp2tm1.1Bird model (CreLox-deletion of exon3-4 deletion). Behavioral studies in female Mecp2tm1.1Bird mice show that the heterozygous mice have motor imbalance, gait deficits, breathing abnormalities, and impaired cognitive function. Extracellular field recordings in hippocampal slices from 6-month old female Mecp2 mice displayed a reduction in long-term potentiation (LTP) at the Schaffer collateral-CA1 synapse. Given that MeCP2 protein regulates gene expression, quantitative polymerase chain reaction (qPCR) analysis was employed here using hippocampal tissue from 4 and 10-month old female Mecp2tm1.1Bird. qPCR analysis revealed a reduction in three known genes regulated by MeCP2: Bdnf, Sapap3, and Kir4.1. A reduction in mRNA coding for synaptic markers Psd95 and synaptophysin was also detected along with upregulated mRNA levels for glutamate receptors (Glur1, Glur2, Nr2a, and Nr2b). Altogether, this integrative analysis suggests that female Mecp2 mice displayed significant behavioral and synaptic plasticity deficits, along with robust alterations in gene expression that can be utilized as disease readouts for preclinical testing.

 

Abstracts & Publications

  • PsychoGenics
  • 215 College Road, Paramus, NJ 07652
  • Tel: (914) 406-8000
  • Fax: (914) 406-8090