Emerging Concepts and Functions of Autophagy as a Regulator of Synaptic Components and Plasticity

Abstract

Protein homeostasis (proteostasis) is crucial to the maintenance of neuronal integrity and function. As the contact sites between neurons, synapses rely heavily on precisely regulated protein-protein interactions to support synaptic transmission and plasticity processes. Autophagy is an effective degradative pathway that can digest cellular components and maintain cellular proteostasis. Perturbations of autophagy have been implicated in aging and neurodegeneration due to a failure to remove damaged proteins and defective organelles. Recent evidence has demonstrated that autophagosome formation is prominent at synaptic terminals and neuronal autophagy is regulated in a compartment-specific fashion. Moreover, synaptic components including synaptic proteins and vesicles, postsynaptic receptors and synaptic mitochondria are known to be degraded by autophagy, thereby contributing to the remodeling of synapses. Indeed, emerging studies indicate that modulation of autophagy may be required for different forms of synaptic plasticity and memory formation. In this review, I will discuss our current understanding of the important role of neuronal/synaptic autophagy in maintaining neuronal function by degrading synaptic components and try to propose a conceptual framework of how the degradation of synaptic components via autophagy might impact synaptic function and contribute to synaptic plasticity.

Keywords: aging; autophagy; memory; mitochondria; mitophagy; neurodegeneration; neurons; proteostasis; synapse; synaptic plasticity.

Figure 1

Emerging concepts and functions of how autophagy might regulate synaptic components and synaptic plasticity. Synaptic components (in red, outlined in the white rectangle within the presynapse) including synaptic proteins (PSD-95, PICK1 and SHANK3), synaptic vesicles, postsynaptic receptors (GABAA receptors and AMPA receptors following endocytic removal from the plasma membrane) and mitochondria are known to be degraded (straight line) by autophagy (in green), thereby potentially contributing to different forms synaptic plasticity (in purple, outlined in an oval-shaped frame) such as long-term potentiation (LDP), long-term depression (LTD) and memory formation. Ubiquitin-proteasome system (in blue) and endosomal-lysosomal system (in blue) also degrade (dotted lines) certain synaptic components and, thus contribute to synaptic plasticity and memory.