ReviewNeuronal Autophagy in Synaptic Functions and Psychiatric Disorders
Section snippets
Canonical Roles of Autophagy in Neuronal Viability and Neurodevelopment
Basal autophagy activity is critical to the maintenance of neuronal homeostasis and viability. Evidence supporting this view originally came from cell biology and animal studies. In postmitotic neurons, the autophagosomes are continuously formed at the distal end of the axon and undergo unidirectional transport along microtubules toward the soma, which is enriched with lysosomes and biosynthetic machinery responsible for producing building blocks for life (e.g., amino acids, lipids) 15, 16, 17,
Role of Autophagy in Synapse Remodeling and Synaptic Plasticity
Maintaining the integrity of proteins (e.g., synaptically localized proteins, neurotransmitters and their receptors) and organelles (e.g., synaptic vesicles, mitochondria) is crucial to sustain neuronal functionality throughout their lifetime, which could span over a century in the case of humans. Besides, highly polarized and extended morphologies of neurons pose a unique spatial challenge for coordinating the local homeostatic need for autophagic clearance. Recent cellular imaging studies
Neuronal Autophagy in the Regulation of Memory, Cognition, and Psychiatric Manifestations
Although we discussed the roles of autophagy in synaptic plasticity, what is the direct evidence supporting the role of autophagy in higher brain functions, such as learning, memory, or cognition? Cellular autophagic activity is known to gradually decrease during normal aging (77). Spermidine, an endogenous substance with autophagy-inducing activity, has been reported to extend longevity in many species (78) and could protect from aging-associated memory impairment and metaplasticity (i.e.,
Future Perspective
These studies have broader implications in neurological and neuropsychiatric disorders. Elevated levels of p62 proteins or p62-positive protein aggregates in the nervous system may represent a molecular signature shared across these two disease categories. For example, a rodent model of 22q11.2 chromosomal deletions, which are at high risk of developing schizophrenia or early onset PD 98, 99, exhibits elevated expression of p62 and alpha-synuclein proteins in the prefrontal cortex or substantia
Acknowledgments and Disclosures
This work was supported by National Institutes of Health Grant Nos. MH-092443 (to AS), MH-094268 (to the Silvio O. Conte Center), MH-105660 (to AS), and MH-107730 (to AS); foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation (to AS); and Department of Defense/Congressionally Directed Medical Research Programs Grant No. W81XWH-11-1-0269 (to TT).
We thank Dr. Akiko Sumitomo for comments and artwork for the Figures.
The authors report no biomedical financial
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