Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association.

Axon terminals control endolysosome diffusion to support synaptic remodelling

Endolysosomes are acidic organelles formed by the fusion of endosomes with lysosomes. In the presynaptic compartment they contribute to protein homeostasis, the maintenance of vesicle pools and synaptic stability. Here, we evaluated the mobility of endolysosomes found in axon terminals of olfactory sensory neurons of Xenopus tropicalis tadpoles. F-actin restricts the motion of these presynaptic acidic organelles which is characterized by a diffusion coefficient of 6.7 × 10−3 μm2·s−1. Local injection of secreted protein acidic and rich in cysteine (SPARC) in the glomerular layer of the olfactory bulb disrupts the structure of synaptic F-actin patches and increases the presence and mobility of endolysosomal organelles found in axon terminals. The increased motion of endolysosomes is localized to the presynaptic compartment and does not promote their access to axonal regions for retrograde transportation to the cell body. Local activation of synaptic degradation mechanisms mediated by SPARC coincides with a loss of the ability of tadpoles to detect waterborne odorants. Together, these observations show that the diffusion of presynaptic endolysosomes increases during conditions of synaptic remodelling to support their local degradative activity.

A 5′ UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation

RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5′ UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons.

A 5’ UTR G-quadruplex controls localisation and translation of a potassium leak channel mRNA

ABSTRACTRNA G-quadruplexes (G4s) are non-canonical secondary structures that have been proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within 3’ UTRs of some neuronal mRNAs are known to control their distal localisation and local translation, contributing to the distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5’ UTR of KCNK9 mRNA, encoding the potassium 2-pore domain leak channel Task3. Using circular dichroism, we show that this (GGN)13 repeat forms a parallel G4 that exhibits the stereotypical potassium specificity of a G4, remaining thermostable under physiological ionic conditions. The G4 is inhibitory to translation of Task3, which can be overcome through the activity of the G4-specific helicase DHX36, consequently increasing K+ leak currents and decreasing resting membrane potentials in HEK293 cells. Additionally, we observe that this G4 is fundamental to ensuring the delivery of Task3 mRNA to distal primary cortical neurites. It has previously been shown that abnormal Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is required for regulated local expression of Task3 leak channels that maintain K+ leak currents within neurons.

LTP induction boosts glutamate spillover by driving withdrawal of astroglia

SUMMARYExtrasynaptic actions of glutamate are limited by high-affinity transporters on perisynaptic astroglial processes (PAPs), which helps to maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodelling, but how this remodelling affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localisation reveal that LTP induction thus prompts a spatial retreat of glial glutamate transporters, boosting glutamate spillover and NMDA receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which synaptic potentiation could alter signal handling by multiple nearby connections.

Memory beyond the synapse

Based on studies of the molecular and cellular cascades that occur during memory consolidation for a one-trial passive-avoidance learning task in the young chick, I review the evidence that memory is encoded in permanent changes in synaptic connectivity in a specific brain region, the Hebb hypothesis. I conclude that despite the fact that such a cascade occurs, culminating in the synthesis of cell-adhesion molecules that are involved in synaptic remodelling, synaptic events are not in themselves sufficient to account for the phenomena of memory. Both whole brain (neuromodulator) and whole body (hormonal) processes are engaged. Memories are labile, disarticulated and stored in a distributed manner; how the mind/brain recreates coherent memories from this pattern is a mystery.