ACTIN BINDING PROTEIN DREBRIN MAY STABILIZE ACTIN FILAMENTS IN DENDRITIC SPINES WHEN NEURONS GET STRESSED

Abstract

Loss of synaptic connectivity is currently considered as being the best neurobiological correlate of age-induced mild memory loss (mild cognitive impairment), frequently seen as a prodromal stage of Alzheimer's disease. Cognitive skills, in turn, require synaptic plasticity resulting in morphological adaptations of dendritic spines coordinated via filamentous actin (F-actin) cytoskeleton remodelling. Consequently, several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilizing protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Notably, since a sharp decrease in DBN levels is correlated with cognitive deficits associated with mild cognitive impairment, Down syndrome and Alzheimer's disease (Shim & Lubec, 2002; Counts et al. 2012), we hypothesized that DBN protein abundance instructs the integrity and function of spines. We created and analyzed a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. In contrast to a previous study, we found no changes in synaptic density, function or plasticity in DBN deficient mice, which may indicate robust compensatory mechanisms that safeguard cytoskeleton homeostasis at the synapse (Willmes et al. 2017). However, challenging the F-actin cytoskeleton in culured hippocampal neurons with an inhibitor of actin polymerization (Latrunculin B) led to a substantial spine loss only in DBN-knockout neurons. Age-induced stressors or pathological insults may thus differentially harm neurons with varying DBN levels. ‘Successful aging’ (cognitive healthy) may separate from ‘un-successful aging’ (cognitive impaired) by the degree spines are able to maintain F-actin homeostasis under less-favorable conditions.