Calcium signalling in TDP-43 models of motor neurone disease and frontotemporal dementia

Motor neurone disease (MND) and frontotemporal dementia (FTD) are terminal neurodegenerative diseases, with rapid disease progression. Clinically, patients present with overlapping symptoms, and the diseases share underlying genetic features and pathophysiology. Notably, pathological changes in neuronal excitability and calcium dynamics have been reported in disease. Furthermore, these signalling changes are implicated in neuronal death present in motor neurone disease and frontotemporal dementia. However, the current literature is unclear as to the nature of these excitability changes, with some studies suggesting that hyperexcitability leads to excitotoxicity, while others suggest that hypoexcitable neurons are most vulnerable to neurodegeneration. The present study presents two complementary models for investigation of calcium signalling changes in disease and reports on preliminary findings as proof of concept. Firstly, signalling changes were identified in an in vitro model of disease, by co-transducing primary hippocampal neurons with variants of the disease related protein TDP-43 together with the fluorescent calcium sensor jGCaMP7f. Calcium activity was then recorded in a TDP-43 mouse model of disease using the Miniscope miniaturised microscope system. This Miniscope application in a neurodegenerative disease mouse model is the first of its kind in this field. In these models TDP-43 expression reduced calcium response during spontaneous neuronal spiking activity, while increasing signalling synchronicity. These changes occurred through increased sensitivity to neuronal stimulation as well as decreased response to repeat stimulation, suggesting a complex and nuanced relationship between excitability and neurodegeneration. Together, these models provide a promising platform for further study of MND and FTD pathomechanisms.