Elsevier

Neurobiology of Disease

Volume 122, February 2019, Pages 49-63
Neurobiology of Disease

Review
Roles for neuronal and glial autophagy in synaptic pruning during development

https://doi.org/10.1016/j.nbd.2018.04.017Get rights and content

Abstract

The dendritic protrusions known as spines represent the primary postsynaptic location for excitatory synapses. Dendritic spines are critical for many synaptic functions, and their formation, modification, and turnover are thought to be important for mechanisms of learning and memory. At many excitatory synapses, dendritic spines form during the early postnatal period, and while many spines are likely being formed and removed throughout life, the net number are often gradually “pruned” during adolescence to reach a stable level in the adult. In neurodevelopmental disorders, spine pruning is disrupted, emphasizing the importance of understanding its governing processes. Autophagy, a process through which cytosolic components and organelles are degraded, has recently been shown to control spine pruning in the mouse cortex, but the mechanisms through which autophagy acts remain obscure. Here, we draw on three widely studied prototypical synaptic pruning events to focus on two governing principles of spine pruning: 1) activity-dependent synaptic competition and 2) non-neuronal contributions. We briefly review what is known about autophagy in the central nervous system and its regulation by metabolic kinases. We propose a model in which autophagy in both neurons and non-neuronal cells contributes to spine pruning, and how other processes that regulate spine pruning could intersect with autophagy. We further outline future research directions to address outstanding questions on the role of autophagy in synaptic pruning.

Introduction

Neuronal networks are composed of balanced connections between excitatory, inhibitory, and modulatory neurons. These balances are disrupted in a range of neurodevelopmental and neurodegenerative diseases, including autism spectrum disorders (ASD), schizophrenia, drug abuse, Down syndrome and Alzheimer's disease. Understanding the basis of these “synaptopathies” promises deeper insight into pathophysiology of these diseases and improved therapies (Dölen and Bear, 2009).

Within the brain, excitatory glutamatergic neuronal connections often occur between presynaptic release sites located en passant along axons and a postsynaptic site on a dendritic shaft or spine. Mature dendritic spines are typically 0.5–5 μm long with a narrow neck and wider head, and feature a range of shapes due to variations in the size of the head and neck length (Peters and Kaiserman-Abramof, 1970). The spine shape is correlated with the synaptic strength (Matsuzaki et al., 2001), stability (Trachtenberg et al., 2002), and function, as the spine neck segregates biochemical and electrical events between the spine head, where the postsynaptic density and neurotransmitter receptors are located, and the dendritic shaft (Koch and Zador, 1993; Yuste and Denk, 1995; Yuste, 2013).

Each spine is a dynamic structure, and in vivo, spine shape and the presence of the spine itself can change over short (minutes) and long (days to weeks) time scales (Alvarez and Sabatini, 2007; Trachtenberg et al., 2002; Yang et al., 2009). Immature spines, known as filopodia, lack a head, are predominantly observed during synaptogenesis, and presumably develop into mature shapes in an activity-dependent manner (Vaughn, 1989; Yuste and Bonhoeffer, 2004; Ziv and Smith, 1996). This modulation of morphology has led neuroscientists over the past century to postulate that such synapses are critical to memory storage, and that changes in spine structure and synaptic strength underlie forms of learning (Dickstein et al., 2013). Thus, understanding the processes through which dendritic spines are removed and restructured should provide important insights into the formation and maintenance of memories.

Neuronal connections begin to form prenatally and are continually refined throughout life (Huttenlocher and Dabholkar, 1997; LaMantia and Rakic, 1990; Rakic et al., 1986). From mid-embryonic development through adolescence, the number of synaptic contacts throughout the brain increase dramatically. During puberty and into adulthood, however, there is a net loss of synapses in many brain regions. This process, known as synaptic pruning, is critical for the establishment and function of mature neuronal networks. Synaptic pruning appears to occur through multiple mechanisms as discussed below, but generally involves the removal of both pre- and postsynaptic elements (Purves and Lichtman, 1980). The removal of the presynaptic component, however, has been more challenging to measure. Here, we will refer to synaptic pruning as the process in which both the pre-and postsynaptic elements are removed, and refer to spine pruning when only the postsynaptic structure has been measured experimentally.

Postnatal synaptic pruning was initially identified as “resorption” of neurites in Purkinje and granule cells by Ramon y Cajal (Yuste, 2015) and was reemphasized in studies of synapses and axons of the cortex almost thirty years ago (Huttenlocher, 1990; LaMantia and Rakic, 1990; Rakic et al., 1986). Significant insights have been made into mechanisms of synaptic pruning in the peripheral nervous system (neuromuscular junction; NMJ) (Purves and Lichtman, 1980; Sanes and Lichtman, 1999) and in the central nervous system (retinogeniculate synapses) (Huberman, 2007) and cerebellum (Hashimoto and Kano, 2013), and these provide a foundation for the future characterization of pruning in the cerebral cortex. Here we review the literature on synaptic pruning events in these systems and propose research to address the relationship between synaptic autophagy and pruning.

Section snippets

Neuromuscular Junction

The study of the development and maturation of the neuromuscular junction (NMJ) provided many of the discoveries of mechanisms that regulate synaptic pruning. At birth, muscles are innervated by multiple motor axon terminals (Fig. 1A), while the mature NMJ is composed of a single presynaptic input from a motor neuron that synapses on a postsynaptic specialization on the muscle surface. In rodents, “superfluous” axon terminals are removed over the first two postnatal weeks, illustrating

Neuronal autophagy

We have recently reported that macroautophagy may play fundamental roles in synaptic pruning in the cortex (Tang et al., 2014). Here we review evidence suggesting roles for macroautophagy in synaptic pruning, speculate about the mechanism underlying this phenomenon, propose specific directions to answer major outstanding questions on the role of macroautophagy in synaptic pruning, and propose a “unified model” for the roles of neuronal and nonneuronal mechanisms in synaptic pruning based in

Control of neuronal autophagy by mTOR

mTOR participates in two protein complexes, mTORC1 and mTORC2, that are integral to cellular signaling and can be distinguished by their sensitivity to the mTOR inhibitor, rapamycin. Although mTORC2 is critical for nutrient sensing in the periphery (Saxton and Sabatini, 2017) and is involved in plasticity in multiple brain circuits (Bockaert and Marin, 2015; Dadalko et al., 2015), mTORC1 has been most directly linked to the regulation of autophagy (Dunlop and Tee, 2014).

The role for mTOR

Contribution of neuronal mTOR-dependent autophagy to dendritic spine pruning

Alterations in dendritic spine density have been proposed to play a role in the pathophysiology of ASDs. In ASD, human postmortem tissue demonstrates elevated spine densities in the temporal cortex (Hutsler and Zhang, 2010; Tang et al., 2014). Furthermore, in other neurodevelopmental disorders, such as Down, Angelman's, Rett, schizophrenia, and Fragile X syndrome, changes in spine density or morphology are observed in postmortem studies and in animals models (Phillips and Pozzo-Miller, 2015).

Mechanism of autophagic dysfunction in autism

Autophagic dysfunction in neurodevelopmental disorders can occur at different steps of the autophagy pathway (Fig. 2). In many neurodevelopmental disorders where autophagy has been suggested to be deficient, mTOR is hyperactive. These include disorders with mutations in TSC1, TSC2, PTEN, and NF1. In these syndromes, hyperactive mTOR could lead to disrupted autophagosome biogenesis due to decreased ULK1 activity (Ganley et al., 2009; Jung et al., 2009; Tang et al., 2014). Alternatively, a recent

Non-neuronal autophagy contributes to spine pruning

Does autophagy play a role in the second principle of developmental synaptic pruning, non-neuronal contributions? Recently, work from the Yoon laboratory has addressed the role of non-neuronal autophagy in developmental spine pruning (Kim et al., 2017). Kim et al. argue that the reduction in autophagy inferred from postmortem tissue of ASD cases (Tang et al., 2014) may arise from non-neuronal cells such as microglia or astrocytes. Given the role of microglia and astrocytes in normal synaptic

Possible mechanisms for microglial autophagy in synaptic pruning

The importance of microglial autophagy to cortical synaptic refinement emphasizes that autophagy may contribute to both principles of synaptic pruning, including the contribution of non-neuronal cells (Fig. 2). How may microglial autophagy control spine pruning? Microglial-dependent removal of synapses requires (1) active microglial migration, (2) phagocytosis of “tagged” material, (3) intracellular degradation of the phagocytosed components. The culture system used by Kim et al. suggests that

Future directions and conclusions

We have described evidence supporting roles for neuronal and non-neuronal autophagy in synaptic pruning, and their regulation by activity-dependent synaptic competition and the actions of non-neuronal cells. Here, we suggest experimental approaches to define how autophagy contributes to synaptic pruning.

Changes in presynaptic neuronal activity underlie synaptic pruning at the NMJ (Colman et al., 1997; Kopp et al., 2000), CF to PC synapse (Hashimoto and Kano, 2003), and the retinogeniculate

Acknowledgements

OJL is supported by NIMH F30MH114390. Work by the Sulzer lab in this field is supported by the Simons, JPB, and Parkinson's Foundations and NIDA R01 DA007418.

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