Autophagy Impacts Dendritic Spines Differently in Proximal and Distal Dendrites of Hippocampus CA1 Neurons

Autophagy is a cellular protein degradation mechanism essential for neuronal function. Recent work has begun to implicate autophagy in cellular functions beyond preserving homeostasis, such as synaptic plasticity and the regulation of dendritic spines. Work from our lab and others demonstrates that synaptic plasticity in distinct dendritic compartments is in part regulated by the uneven distribution of autophagosomes in CA1 apical dendrites. However, it remains unclear whether autophagy contributes to dendritic spine regulation in different dendritic segments. Here, we investigated the role of autophagy and caspase-3, a protein inhibiting autophagy during NMDA receptor-dependent long-term depression, in the regulation of proximal and distal dendritic spines of CA1 pyramidal neurons. We conducted 3D neuron reconstruction of fluorescently labeled dendrites to analyze the volume, density, and subtype proportions of dendritic spines across compartments in ATG5 and caspase-3 knockout mice. ATG5 knockout mice had larger spines in distal dendrites as compared to proximal dendrites. Caspase-3 knockout mice did not display any difference between proximal and distal spine volume. Only ATG5 knockout mice exhibited reduced spine density as compared to controls. Both ATG5 and caspase-3 knockout mice possessed increased spine volume across all three spine subtypes: thin, stubby, and mushroom, along with a shift in spine subtypes with reduced proportions of thin and increased proportions of stubby and mushroom. These findings suggest that both autophagy and caspase-3 contribute to the regulation of spine volume and morphology. However, only autophagy appears to influence spine density. Moreover, autophagy uniquely regulates spine volume differently in proximal versus distal dendrites.