Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 receptor-deficient Mice.

Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging. The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions. However, the underlying mechanisms that link CB1 activity and memory decline remain unknown. Mitochondrial activity profoundly influences neuronal function, therefore age-dependent mitochondrial activity change is one of the known hallmarks of brain aging. As CB1 receptor is expressed on mitochondria and may regulate neuronal energy metabolism in hippocampus, we hypothesized that CB1 receptors might influence mitochondria in hippocampal neurons. We found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. We also found that Serine 65-phosphorylated ubiquitin, a key marker for mitophagy, was reduced in adult CB1-deficient mice (CB1-KO) compared to those in wild type controls, particularly in CA1 pyramidal cell layer. Transmission electron microscopy (TEM) analysis showed reduced mitophagy-like events in hippocampus of adult CB1-KO. TEM analysis also showed an increase in thin and elongated mitochondria in hippocampal neurons of adult CB1-KO. 3D reconstruction revealed that mitochondrial morphology in adult CB1-KO was altered as represented by an enhanced density of elongated and interconnected mitochondria. Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging. These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.