The actin-cytoskeleton is an essential structural component of all mammalian cells, and involves the constant dynamic cycling between actin monomers and filaments, a process mediated by numerous actin-associated proteins[1]. Tropomyosins are actin-associated proteins that form co-polymers with actin filaments. Here, we aim to determine tropomyosin isoform-specific properties in the brain[2]. We report the expression, localisation and physiological function of various tropomyosin isoforms (and by proxy, their actin filaments) in mouse primary neurons, astrocytes and microglia – with a focus on the post-synaptic isoforms in neurons[3,4]. Behavioural analysis was conducted on tropomyosin knock-out mouse models and identified behavioural alterations in a sex-dependent manner. Using live calcium imaging in primary neurons of tropomyosin knock-out mice, we identified a significant reduction in single cell amplitude, increase in rise and fall time (P<0.001), suggesting a reduction in synaptic strength and a role of tropomyosin in fast spontaneous neuronal firing. Tropomyosin knockout neurons have significantly increased dendritic fields and increased neuronal connectivity and network ensembles (P<0.0001). Tropomyosin knock-out neurons also exhibit significant reductions in receptor internalisation (63% reduction, P<0.05), suggesting a role in endocytosis. We further found that targeting of postsynaptic tropomyosin leads to a reduction in the uptake of pathological forms of tau protein, which is observed during disease progression in tau-related dementias. Identifying and targeting this pathway can therefore have significant implications for the development of disease-modifying therapies to slow or halt pathological tau spread throughout the brain in tau-related dementias such as Alzheimer’s disease.