Dissociation of Frontotemporal Dementia–Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom?

“…Interestingly, a C9orf72 model [23] and a PGRN model [34] showed increased anxiety compared to their littermate by showing increased thigmotaxis in an open field. In line with the emotion-blunting and fear-conditioning deficit in FTD [35], a PGRN-deficient FTD mouse model [36] and 2 tau mutation-based mouse models [37] showed decreased fear conditioning in an amygdala-dependent cued fear-conditioning test. The 5-choice serial reaction time task is based on the capacity of a mouse to wait for a delay between the stimulus and the response to get the reinforcer and is a test of impulsivity dependent on the prefrontal cortex [38].…”

“…The 3-chamber sociability test has been widely used in autism models and also in FTD models [29,30,36]. In this paradigm, the tested mouse is placed in the central chamber of a 3-chamber apparatus and allowed to explore the other rooms either containing an unknown mouse or empty.…”

“…The time spent interacting with the unknown mouse indicates the social interest of the tested mouse. Two different PGRN-deficient FTD models, a C9orf72 model and a mutated CHMP2B-based mouse FTD model, showed impaired social interest in this paradigm [23,29,30,36]. Measurement of social interactions with an unknown mouse in the home cage (the resident intruder paradigm) also showed decreased social interest in 3 bvFTD models [30,55,56].…”

“…The mouse is placed in the center of the platform where it learns to locate the target. Spatial memory defects were detected using the Morris water maze and the Barnes maze in 2 PGRN-deficient mouse lines [29,55], 1 TDP-43 overexpression line [86] and 1 mutant tau line [87], but 2 other PGRN-deficient mouse lines did not show spatial memory deficit [36,56]. …”

Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

“…Pathologically, Grn −/− mice exhibit increased expression of proinflammatory cytokines and exacerbated microglial activation and astrogliosis, all of which are also observed in patients with FTD (8,9). However, heterozygous Grn mice recapitulate some, but not most, aspects of the disease (10).…”