Elsevier

Biological Psychiatry

Volume 87, Issue 9, 1 May 2020, Pages 787-796
Biological Psychiatry

Review
Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders

https://doi.org/10.1016/j.biopsych.2019.07.018Get rights and content

Abstract

Homeostatic maintenance of physiological functions is fundamental to organismal well-being. Disruption or imbalance in homeostasis results in functional disturbances at molecular, cellular, and tissue levels, leading to manifestation as physical and mental illnesses. Homeostatic imbalance is caused by a range of pathophysiological mechanisms, including disrupted reduction-oxidation reactions, inflammatory responses, metabolic disturbances, or failure in quality control of cellular proteins and organelles. However, the roles for the protein/organelle quality control in the regulation of behaviors, in particular of cognitive processes, had not been well documented, until recent reports finally supported this concept. The frontline studies in neuroscience have revealed that synaptic components (e.g., synaptic proteins, organelles, neurotransmitters and their receptors) are selectively degraded by autophagy, a cellular recycling machinery implicated in surveillance and quality control of proteins and organelles responsible for the maintenance of cellular homeostasis. Apart from the canonical role of autophagy in supporting cell viability, synaptic autophagy appears to regulate synapse remodeling and plasticity. Consistently, emerging evidence suggests novel roles of autophagy in memory encoding, information processing, or cognitive functions. In this review, we overview recent progress in understanding the roles of neuronal autophagy in homeostatic maintenance of synaptic functions, with particular focus on how disruptions in these processes may contribute to the pathophysiology of 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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