Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.