TAR DNA-binding protein (TDP-43) has been identified as the major pathological factor in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We constructed a conditional mouse with depletion of TDP-43 in the forebrain (TDP-43 cKO) and find that the mice exhibit a whole spectrum of age-dependent FTLD-like behavior abnormalities. The development of neurodegenerative pathology in TDP-43 cKO mice is closely associated with their behavior changes, both of which are well correlated with the age-dependent alterations of the cortex transcriptomes. Notably, the transcriptomopathies of the TDP-43 cKO mouse consist of changes of mRNA levels as well as pre-mRNA splicing patterns of many genes. This study not only supports the scenario that loss-of-function of TDP-43 in mice may recapitulate key behaviour features of the FTLD diseases, but also provides a list of TDP-43 target genes/transcript isoforms useful for future therapeutic research.