Elevating Neuronal CYLD Causes Frontotemporal Dementia (FTD)-Relevant Behavioral and Physiological Deficits

Abstract

Frontotemporal dementia (FTD), a leading form of presenile dementia disrupting behavior, language and/or movement, is linked to mutations of a number of genes, including CYLD that encodes a Lys63 (K63) deubiquitinating enzyme. Among several CYLD variants found in FTD patients, a gain-of-function missense mutant, M719V, has been proposed to be pathogenic, but its pathogenicity in vivo and the underlying mechanism remain unknown. Here, we have developed transgenic mice that express either wildtype (WT) or M719V-CYLD in neurons throughout the mouse brain using adeno-associated virus (AAV) mediated somatic brain transgenesis. We show that somatic M719V-CYLD transgenic mice display profound FTD-associated behavioral impairments, including risk-taking, reduced social interaction, and loss of empathy that emerge from early stages and worsen with aging. Furthermore, M719V-CYLD mice also show significant early neurophysiological impairments in the prefrontal cortex (PFC), including depolarized resting membrane potential, decreased synaptic transmission, and reduced neuronal excitability. Surprisingly, however, M719V-CYLD mouse brain exhibits elevated autophagy activity and decreased Akt-mTOR signaling without overt neuronal cell loss or microgliosis even at 12 months of age. Most M719V-CYLD-associated cellular and behavioral phenotypes are also recapitulated but to a lesser extent in WT-CYLD mice, suggesting CYLD activation is responsible for the observed neural circuit deficits and the M719V mutation is gain-of-function in nature. Our results uncover important roles of neuronal CYLD in PFC function and social behaviors and establish a unique animal model to investigate pathogenic mechanisms of FTD, in particular its social behavioral deficits, at molecular, cellular, synaptic and circuit levels.