br Autophagy at the Synapse The synapse is a

Autophagy at the Synapse The synapse is a highly specialized neuronal compartment that forms the basic unit of communication between neurons. Communication relies on electrical signals that are propagated down the axon of the presynaptic neuron, where they trigger the quantal release of neurotransmitters into the synaptic cleft to elicit activity on the postsynaptic neuron. Both the presynaptic button and the postsynaptic density are specialized compartments, packed with molecules that are unique and dedicated to serving their function in neuronal communication. For example, presynaptic buttons are packed with synaptic vesicles containing neurotransmitters, as well as the machinery that allows fusion of these vesicles with the plasma membrane and the retrieval of fused vesicle membranes by endocytosis. On the other side of the synaptic cleft, highly specialized postsynaptic densities contain a high density of the receptors activated by the neurotransmitters, as well as scaffold, cytoskeletal, and signalling molecules, to ensure the activation of the postsynaptic neuron. In many neurons, including the pyramidal neurons of the neocortex, postsynaptic densities are mostly located on protrusions or outgrowths of dendritic shafts, known as dendritic spines, which increase the efficacy of neurotransmission [10]. The number of dendritic spines is developmentally regulated. In the mouse, synaptogenesis in the first 3 postnatal weeks is followed by a period of spine pruning that occurs between postnatal days 20 and 30 and is crucial for the proper wiring of the adult TCEP [11].
Regulation of Neuronal Autophagy
Secretory Autophagy in Neurons? In addition to degradation, autophagy may also constitute an unconventional secretory pathway, facilitating the secretion of proteins such as interleukin-1b or galectins that lack signal peptides [85] and has been reviewed elsewhere [86]. Briefly, secretory autophagy was shown to depend on Atg5 85, 87 and is believed to require most other proteins that participate in the nucleation and elongation of autophagosomes. The parting between the degradative and secretory routes likely depends on trafficking molecules that direct autophagosomes either to the lysosome or alternatively to the plasma membrane. For example, while the small GTPase Rab8a, a regulator of polarized sorting to the plasma membrane, was shown to be needed for secretory autophagy 85, 88, its closely related isoform Rab8b is more important for degradative autophagy [89]. More recently, it has been suggested that targeting of autophagosomes to the plasma membrane depends on the interaction of Sec22b, a SNARE protein anchored on the outer membrane of secretory autophagosomes, with syntaxin 3/4 as well as SNAP-23/29 on the plasma membrane [90]. Neurotransmission and communication between neurons and other cell types requires the controlled release of molecules from synaptic vesicles and large dense-core vesicles. It remains unclear whether secretory autophagy represents an additional secretory route in neurons, which is employed under physiological and/or pathological conditions (Figure 3). Recent studies have suggested that secretion of mutant huntingtin, cytosolic amyloids, and a-synuclein may rely on mechanisms dependent on prelysosomal compartments, the molecular nature of which has not yet been determined 91, 92, 93. In addition, secretory autophagy has also been implicated as an unconventional mechanism for the insertion of proteins into the plasma membrane. One such example is Mpl, the receptor for thrombopoietin, which plays a crucial role in megakaryocytic differentiation and maturation. While the fully glycosylated, mature Mpl receptor follows the canonical secretory pathway, the core-glycosylated, immature protein is inserted into the plasma membrane by secretory autophagy [94]. In addition, hundreds of neuronal surface membrane proteins, which include a substantial fraction of surface GABAA receptor or AMPA-type and NMDA-type glutamate receptor subunits, are core-glycosylated, thus exhibiting unconventional secretory processing [95]. This results in the neuronal membrane and synaptic sites displaying high levels of glycosylation profiles that are classically associated with immature intracellular proteins [95]. Whether the trafficking of these core-glycosylated receptors to the postsynaptic density or other neuronal sites requires some autophagic intermediate is a very exciting possibility that remains to be addressed. Exploring the regulation of secretory autophagy in neurons and the nature of its cargo can add new dimensions in neuronal communication and in delineating the roles of autophagy in neuronal function and dysfunction.