PROGRANULIN KNOCK-OUT MICE SHOW SYMPTOMS REMINISCENT OF FRONTOTEMPORAL DEMENTIA

Abstract

Background: Frontotemporal dementia (FTD), the second most common age-related cognitive decline, has strong genetic underpinnings. Mutations in the progranulin gene reflect 10-15% of genetically identified casesdue to haploinsufficiency of gene products. A preclinical model that may reiterate the FTD phenotype was assessed in a battery of behavioural tests to explore whether: i) hemizygous mice deficient in progranulin reiterate symptoms of FTD. ii) progranulin knock-down or knock-out enhances susceptibility to inflammatory stress (chronic lipopolysaccharide treatment) and results in accelerated phenotypes. Methods: Grn deficient mice were maintained on a C57Bl/6 background and bred in both homozygous and heterozygous cohorts. Prior to assessment in a battery of behavioural tests, mice were treated with vehicle or lipopolisaccharide (LPS, 500 m g/kg daily ip) for 5 weeks. Cohorts were divided into females and males undergoing a series of motor (rotarod, catwalk, home cage activity monitor), emotional (elevated plus maze, social interaction, socially transmitted flavour preference, sucrose preference test) and cognitive tasks (water maze spatial learning, object recognition; social learning of flavour). Results: When tested at the age of 6 months, subtle behavioural deficits were detected in heterozygous, but less in homozygous KO mice. These included weight reductions, lower food consumptions, hyperactivity in the home cage but no circadian anomalies, deficits in cognitive flexibility but no overall spatial learning impairment, subtle motor learning deficits and gait anomalies, lower levels of anxiety but no anhedonia, and reduced sociability. There was no effect of LPS despite the induction of inflammatory responses in control brains. Conclusions: The Grn deficiency model presents with some FTD relevant phenotypes that were revealed here much earlier than in previous reports, but an enhanced susceptibility towards inflammatory agents and a resultant accelerated phenotype was not confirmed. Stronger deficits in heterozygous cohorts confirm that haploinsufficency is an appropriate FTD approach. For homozygous knock-out mice a stronger compensatorymechanismsmay be assumed. Alternatively, complete GRN loss in human patients may induce adult lipofuscinosis expressed as epileptic events and global ataxia, but not all lipofuscinosis variants express cognitive decline. Older cohorts may be instructive in a dissociation of symptoms. Supported by SULSA and TPP Global Development.