Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice

Nagy et al. Alzheimer's Research & Therapy https://doi.org/10.1186/s13195-019-0540-x (2019) 11:88 RESEARCH Open Access Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice Dávid Nagy1, Lauren Herl Martens2, Liza Leventhal2, Angela Chen2, Craig Kelley1, Milan Stoiljkovic1 and Mihály Hajós1* Abstract Background: Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. Methods: The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic—medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months. Results: Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation. Conclusion: Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia. Keywords: Frontotemporal dementia, Progranulin, Electrophysiology, Reward-seeking/processing, Prefrontal cortex Background Frontotemporal dementia (FTD) is the second most frequent cause of dementia and one of the most common forms in patients under the age of 65 [1]. FTD is clinically defined by progressive changes in behavior and personality, language deficits, cognitive decline, and eventual death [2]. Pathologically, FTD is characterized by focal brain mass loss in the frontal and temporal lobes, hypoperfusion in the affected brain regions, gliosis, neuronal inclusions of various aggregated proteins, and neuronal loss in the affected regions [3, 4]. Approximately 50% of FTD cases have a familial origin with mutations in MAPT, GRN, and C9ORF72 causing the majority of these cases [2, 5]. * Correspondence: 1 Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06520, USA Full list of author information is available at the end of the article Mutations in the progranulin (GRN) gene were causatively linked to FTD in 2006 and account for 5–10% of all FTD cases [6–8]. Disease-causing mutations span the gene and result in one non-functional allele, thereby making the mutations loss of function [8]. The resulting ≥ 50% reduction in the systemic protein levels indicates that progranulin (PGRN) haploinsufficiency is causative for FTD-GRN [9]. Pathology associated with FTD-GRN includes TDP-43 aggregates (TDP type 1) [10, 11]. In MRI imaging studies, FTD-GRN patients have consistent asymmetric frontal, temporal, and parietal lobe volume reductions [12]. FTD-GRN also presents with a significant amount of neuroinflammation [13]. Interestingly, patients carrying two mutant GRN alleles present with adolescent-onset neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder [14]. Recently, it has been demonstrated that Grn+/− mutation carriers with FTD © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nagy et al. Alzheimer's Research & Therapy (2019) 11:88 also have lysosomal abnormalities and increased lipofuscin in their retinas, lymphoblasts, fibroblasts, and postmortem brain tissue [15]. The fact that differences in systemic PGRN levels result in different diseases, including FTD, NCL [16], and cancer [17], indicates that PGRN levels require strict regulation. Progranulin, a secreted growth factor, plays roles in multiple cellular processes including development, cell survival, inflammation, and wound repair [17]. In the CNS, PGRN is expressed by neurons and microglia and functions as a neurotrophic factor and inflammatory mediator [18]. Multiple mouse models of progranulin deficiency have been generated and characterized in order to begin to understand the CNS functions of PGRN, as well as determine their utility for preclinical modeling of FTD [19–21]. As to whether the Grn+/− mice model human FTDGRN has not been extensively investigated. It is clear that Grn−/− mice develop age-dependent neuropathology in the thalamus, hippocampus, and cortex that includes gliosis and ubiquitin-positive aggregates [19, 20, 22], whereas the Grn+/− mice do not develop any frank neuropathology, even at 2 years of age [19]. Each mouse model has been extensively tested in batteries of behavioral assays; however, deficits in social interactions are the one consistent test where reductions are observed across different models [19, 20, 22]. It has been demonstrated that the Grn+/− mice have reduced social behavior, as well as social dominance abnormalities, which has been linked to dysfunction in the amygdala and prefrontal cortex [19, 23]. In this study, we investigated whether alterations in the underlying neuronal physiology are associated with regions of neuropathology in the PGRN-deficient mice. We focused on the thalamocortical circuitry, which is known to be affected in FTD and has been reported to be associated with complement-mediated synaptic loss in Grn−/− mice [24]. The dorsomedial (DM) thalamus receives input and sends major outputs to the amygdala, the region of the limbic system most often associated with emotional and social behavior, as well as to the prefrontal cortex, a region associated with executive function and behavioral inhibition [25]. Lesion studies in rats and monkeys have concluded that damage to the DM thalamus is linked to problems with behavioral flexibility and deficits in developing new behavioral strategies to obtain rewards [25]. In fact, FTD patients are known to have deficits in reward-seeking behaviors such as overeating, hypersexuality, and alcohol abuse [26, 27], and these deficits were linked to impairment of the thalamocortical feedback loop [28]. Therefore, based on the profound thalamic neuropat (...truncated)