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

Abstract：

: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, and 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. Here, we found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. 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 that mitochondrial morphology in adult CB1-KO mice was altered shown by an increase in thin and elongated mitochondria in hippocampal neurons. 3D reconstruction of mitochondrial morphology after scanning electron microscopy additionally revealed an enhanced density of 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.

journal_name

Brain Res Bull

journal_title

Brain research bulletin

authors

Kataoka K,Bilkei-Gorzo A,Nozaki C,Togo A,Nakamura K,Ohta K,Zimmer A,Asahi T

doi

10.1016/j.brainresbull.2020.03.014

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

40-49

eissn

0361-9230

issn

1873-2747

pii

S0361-9230(20)30138-6

journal_volume

160

pub_type

杂志文章

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