Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons

Adrienne Mary Grech; Xin Du; Simon S Murray; Junhua Xiao; Rachel Anne Hill

doi:10.1016/j.bbr.2019.111984

Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons

Behav Brain Res. 2019 Oct 17:372:111984. doi: 10.1016/j.bbr.2019.111984. Epub 2019 May 28.

Authors

Adrienne Mary Grech¹, Xin Du¹, Simon S Murray², Junhua Xiao², Rachel Anne Hill³

Affiliations

¹ Department of Psychiatry, School of Clinical Sciences, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
² Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia.
³ Department of Psychiatry, School of Clinical Sciences, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. Electronic address: Rachel.hill@monash.edu.

PMID: 31150746
DOI: 10.1016/j.bbr.2019.111984

Abstract

Schizophrenia is a debilitating disorder characterised by three main symptom categories: positive, negative and cognitive. Cognitive symptoms emerge first, and currently do not have appropriate treatments, despite being a strong predictor of the severity and progress of the illness. Cognitive deficits are strongly associated with the dysfunction of GABAergic parvalbumin interneurons (PV-IN). PV-IN are supported by Brain-Derived Neurotrophic Factor (BDNF) via its receptor Tropomyosin-related Kinase B (TrkB). The main aim of this study was to investigate the cognitive and affective consequences of disrupted BDNF-TrkB signalling at PV-IN. We crossed PV-Cre mice with heterozygous TrkB floxed mice (PV-Cre:Fl^+/-) to knock-down TrkB receptors on PV-IN. Male and female mice underwent a battery of tests including: Y-Maze, Cheeseboard Maze, Elevated Plus Maze, and Locomotor activity. Co-expression of PV and TrkB in the hippocampus was assessed by fluorescent immunohistochemistry and detailed stereology. Sex-specific spatial memory impairments were found in the Y-Maze. Only male PV-Cre:Fl^+/- mice showed no preference for the novel arm. Furthermore, there was a male specific genotype difference in memory retrieval in the Cheeseboard Maze. Male PV-Cre:Fl^+/- mice were more preservative in their learning than male PV-Cre control mice. Overall, the evidence from this study suggests that sex had a developmental influence on this constitutive model. Male spatial memory was altered by the disruption to BDNF-TrkB signalling at PV-IN. This aligns with males showing more severe cognitive dysfunction in schizophrenia.

Keywords: BDNF; Hippocampus; Learning; Memory; Parvalbumin; TrkB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / physiology
Brain / metabolism
Brain-Derived Neurotrophic Factor / metabolism*
Brain-Derived Neurotrophic Factor / physiology
Cognition / physiology
Female
GABAergic Neurons / metabolism
Hippocampus / metabolism
Interneurons / metabolism*
Male
Membrane Glycoproteins / metabolism*
Memory Disorders
Mice
Mice, Inbred C57BL
Parvalbumins / metabolism
Protein-Tyrosine Kinases / metabolism*
Signal Transduction / physiology
Spatial Memory / physiology*

Substances

Brain-Derived Neurotrophic Factor
Membrane Glycoproteins
Parvalbumins
Ntrk2 protein, mouse
Protein-Tyrosine Kinases