Rodent Models of Frontotemporal Dementia

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that results in frontotemporal dementia (FTD), the second most common form of early-onset dementia after Alzheimer's disease. Characterized by significant behavioral, cognitive, and linguistic impairments, FTD typically manifests between the ages of 45 and 65 and encompasses a spectrum of clinical subtypes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). The underlying pathology involves a range of proteinopathies, predominantly TDP-43, tau, and FUS, with genetic mutations in MAPT , GRN , C9orf72 , VCP , and TARDBP playing critical roles in disease onset and progression. This chapter provides a comprehensive overview of FTD's clinical presentation, neuropathology, and genetic landscape, followed by an in-depth discussion of rodent models developed to replicate the disease's complex features. Genetic mouse models targeting mutations in GRN , VCP , TARDBP , MAPT , and C9orf72 are highlighted, emphasizing their unique contributions to our understanding of FTD pathogenesis. Each model is discussed in terms of behavioral phenotypes, neuropathological changes, and their utility in mimicking specific subtypes of FTLD. The chapter also examines the salience network disruptions and social, cognitive, and emotional dysfunctions observed in these models, which mirror key aspects of human disease. Despite the limitations of species differences and lifespan constraints, rodent models remain invaluable tools for studying the molecular mechanisms underlying FTD and for identifying potential therapeutic targets. As preclinical models become more refined and our understanding of disease mechanisms expands, these models are poised to play a pivotal role in guiding the development of effective interventions for FTD.