Research Lab

Local Protein Synthesis in Information Processing and Memory

Memory formation requires the synthesis of new proteins, which are the basic building blocks and function executors. In the textbook view, proteins are made in the cell body and are then quickly localized to sites of action. However, neurons have highly polarized structures that helps wiring up the brain. These long neuronal processes pose a logistic challenge on delivering proteins to synapses far from the cell body. In the extreme case of corticospinal tract, axons can be over a meter long. This prompted the discovery of on-demand local protein synthesis (e.g. Wong et al, Neuron 2017; Cagnetta, Wong et al, Mol Cell 2019). Perplexingly, clinical trials targeting protein-synthesis-related pathways have shown both failures and promises, indicating our understanding is incomplete. Traditionally, postsynaptic protein synthesis has been prominently featured in disease models. But little is known for presynaptic, or axonal, translation in both health and disease. Our recent work uncovered that axonal translation sustains neurotransmission in cortical circuits (Wong et al., Neuron 2024; Wong et al., Nat Protoc 2025), hinting there is an urgent need for axon-inclusive models in therapeutic targeting. To address this, we will elucidate where, when and what synaptic protein synthesis in axons regulates cortical neurotransmission.

Unconventional Synaptic Signalling

In neuroscience, Hebbian Postulate is famous for providing a framework for understanding brain wiring, plasticity, and memory. This was succinctly paraphrased by Carla Shatz as “cells that fire together, wire together”. But how do cells know that they are firing together? It is widely thought to be mediated by the N-methyl-D-aspartate receptor (NMDAR). This “memory receptor” requires the binding of glutamate, a neurotransmitter released during presynaptic cell firing. In addition, due to electrochemical-gradient-mediated Mg²⁺ blockade of the NMDAR channel, postsynaptic cell firing is required to relieve the blockade for NMDAR activation. This coincidental detection therefore assumes that NMDARs are only found at the postsynaptic compartment. Enigmatically, increasing evidence has shown that NMDARs are also found on the presynaptic side (Wong et al., J Physiol 2021; Wong et al., eLife 2021). We recently revealed that presynaptic NMDARs engage local mRNA translation to sustain high- but not low-frequency neurotransmitter release (Wong et al., Neuron 2024). As high-frequency presynaptic firing is critical to memory formation and information conveyance, we will elucidate the molecular pathway that links the presynaptic NMDAR and local translation. We will also explore another long-standing question in the field — how a small quantity of nascent proteins mysteriously confers functional impacts.

Neural Network Alterations in Neurological Disorders

It is often featured that the transmitting neurons excite the recipient neurons. In the neocortex, excitatory neurons indeed account for ~80% of brain cells. Perhaps unsurprisingly, much of the earlier work has been dedicated to this framework of neuronal firing and excitation cascades, which transmit signals and enable long-term plasticity. However, inhibitory neurons are increasingly recognized in information processing, such that the brain requires a healthy balance of excitation-inhibition (E-I). In contrast, E-I imbalance is now a known issue in a wide range of neurological disorders, including autism spectrum disorder and epilepsy. Yet, we have only scratched the surface of inhibitory neuron regulation. For instance, we surprisingly found that activation circuit of inhibitory cells is vastly different compared to the canonical circuit of excitatory cells (Chou, Wong et al., The Innovation 2025).  We also found that contrary to excitatory synapses onto excitatory cells, excitatory synapses onto inhibitory cells are resistant to protein synthesis blockade (Wong et al., Neuron 2024). These differential properties open new doors to disease targeting. With our high-throughput synapse interrogation expertise, we will uncover unappreciated principals of inhibitory neuron regulation and E-I balance in health. And, importantly, how these are altered and may be targeted in pathologies.

1. 1. Wong HH^#, Watt A, Sjöström PJ^#. Laser microsurgery for presynaptic interrogation. Nature Protocols. 2025 Feb 7.
   2. Chou CYC, Wong HH, Guo C, Boukoulou K, Huang C, Jannat J, Klimenko T, Li V, Liang T, Wu V, Sjöström PJ (2025). Principles of visual cortex excitatory microcircuit organization. The Innovation 6(1)
   3. Wong HH^#, Watt A, Sjöström PJ^# (2024). Synapse-specific burst coding sustained by local axonal translation. Neuron 112(2)
      • Featured article in Neuron 112(2)
      • Featured in Research Highlights by Shari Wiseman, Chief Editor, in Nature Neuroscience 27(9) (Link)
      • Press release (Link)
   4. Cagnetta R, Wong HH, Frese CK, Mallucci G, Krijgsveld J, Holt CE (2019). Noncanonical modulation of eIF2 pathway controls an increase in local translation during neural wiring. Molecular Cell 73(3)
   5. Wong HH, Lin JQ*, Ströhl F*, Roque CG, Cioni, JM, Cagnetta R, Turner-Bridger B, Laine R, Harris WA, Kaminski CF, Holt CE (2017). RNA docking and local translation regulate site-specific axon remodelling in vivo. Neuron 95(4)
      • Featured article in Neuron 95(4)
      • Highlighted 5 times by Faculty of 1000 (Link)
      • Featured in Cell Press Selections 2017: The Dynamic Neuron (Link)

* Equal contributions, # Co-corresponding authors