Knock-out of Tpm4.2/Actin Filaments Alters Neuronal Signaling, Neurite Outgrowth, and Behavioral Phenotypes in Mice.

Tropomyosins (Tpm) are master regulators of actin dynamics through forming co-polymers with filamentous actin. Despite the well-understood function of muscle Tpms in the contractile apparatus of muscle cells, much less is known about the diverse physiological function of cytoplasmic Tpms in eukaryotic cells. Here, we investigated the role of the Tpm4.2 isoform in neuronal processes including signaling, neurite outgrowth, and receptor recycling using primary neurons from Tpm4.2 knock-out mice. Live imaging of calcium and electrophysiology data demonstrated increased frequency, yet reduced strength of single neuron spikes. Calcium imaging further showed an increase in neuronal networks. In vitro assays of Tpm4.2 knock-out neurons displayed impaired recycling of the AMPA neurotransmitter receptor subunit GluA1. Morphometric analysis of neurite growth showed increased dendritic complexity and altered dendritic spine morphology in Tpm4.2 knock-out primary neurons. Behavioral analysis of Tpm4.2 knock-out mice displayed heightened anxiety in the open field test, while the elevated plus maze displayed heightened anxiety only in females. Our study depicts the multi-faceted role of the Tpm4.2 isoform and its co-polymer F-actin population in neurons, with potential implications for better understanding diseases of the nervous system which involve actin cytoskeleton dysfunction.