Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders

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.

Keywords: Aggregate; Autophagy; Cognition; Homeostasis; Psychiatric disorders; Synapse.

Fig. 1.. Schematic diagram of macroautophagy

Upon cellular stress conditions triggered by a range of stress modalities (e.g., nutrient starvation, oxidative stress, accumulation of misfolded or aggregated proteins), mammalian target of rapamycin (mTOR) signaling is suppressed, leading to a cascade of events that contribute to the induction of macroautophagy (e.g., 1. Assembly of autophagy regulatory protein complex on the isolation membrane; 2. Elongation of the isolation membrane to form autophagosomes; 3. Autophagosome trafficking to fuse with the lysosome; 4. Maturation of autolysosome and degradation). Critical autophagy regulatory proteins are depicted in green.

Fig. 2.. Regulators of pre- and post-synaptic autophagy

Neuronal activity upregulates autophagosome formation in the presynaptic compartment, using several presynaptically enriched adaptors (e.g., Endophilin A, Bassoon) and regulatory proteins (e.g., Synaptojanin 1). Example of the synaptic vesicle is depicted; synaptic vesicles selectively tagged by an adaptor protein (e.g., Rab26) are recognized by the pre-autophagosomal structure (①) and engulfed by the autophagosome (②), which is subsequently delivered to the lysosome for degradation (③). Endophilin A and synaptojanin 1 cooperatively recruit autophagy regulatory proteins on the autophagosomal membrane, and Bassoon negatively regulates this process by sequestering Atg5. In the postsynaptic compartment, neuronal activity also induces macroautophagy, causing endocytic removal of neurotransmitter receptors (e.g., AMPAR, GABA_AR) from the plasma membrane (④), possibly via regulation of receptor adaptor proteins (e.g., PICK1, PSD-95, SHANK3). Subsequently, the endosome fuses with the autophagosome (⑤) to form the amphisome, which is delivered to the lysosome for degradation (⑥). Surface levels of GABA_AR could also be regulated by the steady-state levels of p62; cytosolic p62 proteins are normally sequestered by the autophagosome (⑦) and degraded by the lysosome (⑧); however, elevated p62 expression due to reduced autophagy activity causes sequestration of GABARAP (as shown by a dotted line in the post-synaptic compartment), leading to downmodulation of surface levels of GABA_AR.