Frontotemporal dementia (FTD) is a debilitating, age-related neurodegenerative condition caused by frontotemporal lobar degeneration (FTLD), most often accompanied by the accumulation and/or dysfunction of the protein TDP-43 (FTLD-TDP). Aggregation of TDP-43, encoded by the TARDBP gene, occurs with or without concomitant mutations in TARDBP, suggesting that its accumulation represents a convergent mechanism underlying cortical vulnerability in FTD. The mechanisms underlying the detrimental effects of TDP-43 dysfunction are complex and likely involve both gain- and loss-of-function mechanisms, due to alterations in the intracellular compartmentalization and aggregation properties of TDP-43. Despite the availability of cell culture and mouse models of TDP-43 pathology, the precise mechanisms by which TARDBP mutations give rise to cortical dysfunction and cell loss in vivo are not clear. Recent imaging studies implicate a disruption in excitatory and inhibitory (E:I) balance in the cortex of patients with FTD, yet very little work has been done to explore the mechanisms by which this arises in vivo. Recent data generated using knockin and overexpression models of TDP-43 have revealed alterations in gene expression, function, and viability of cortical parvalbumin-expressing fast-spiking interneurons (PV-INs), cells which provide the main source of feed-forward GABAergic neurotransmission in the cortex and are critical for maintaining E:I balance. However, very little is known about the mechanisms underlying PV-IN vulnerability with Tardbp mutations in vivo and how PV-IN dysfunction contributes to pyramidal excitatory neuron function and loss. The experiments proposed in this application aim to identify the effects of TDP-43 mutation on PV-INs by assessing the PV-IN-specific transcriptional changes which occur during the progression of disease in Tardbp mutant knockin mice (Aim 1) and determining the impact of Tardbp mutations on PV-IN properties and cortical E:I balance with age (Aim 2). Differential gene expression and splicing profiles will be generated for PV-INs and compared to other neuron types using cell-type-specific translating ribosome purification protocols, with comparison to publicly available datasets of transcriptional changes in mouse and iPSC models of FTLD-TDP and other FTDs and TDP-43 RNA-binding assay databases. Computer-assisted modeling will be used to generate cell-type-specific protein-protein-interaction networks to identify convergent genes/proteins which could serve as targets for preventing cellular dysfunction. Electrophysiological approaches will explore the contributions of different cell types to the progression of cortical dysfunction, with comparison to a TDP-43 overexpression model to explore whether altered neuronal properties reflect a gain-of-function mechanism. These studies have the potential to reveal the mechanisms by which TDP-43 abnormalities influence cortical function and identify novel genes and/or path...