Mapping the human synaptome: the origins of thought?

National Center for Advancing Translational Sciences via Flickr

The field of neuroscience has grown exponentially since it began. From the humble works of Ramón y Cajal, delicately hand-drawing the first images of human cortical neurons, to the advances by Karl Deisseroth manipulating neural activity using light. This progress is driven by one goal: a complete understanding of the most complex organ in the human body – the brain.

Researchers at the University of Edinburgh are one step closer to achieving this goal. Led by Professor Seth Grant, they have been awarded £1.3 million by the Wellcome Trust and are chartered with the ground-breaking task of mapping the human brain. The success of the project has the potential to enhance our understanding of human thoughts and behaviour and could pinpoint where it all goes wrong in disease.

The group aim is to address their task by creating a human synaptome. This is a map of the trillions of connections between neurons, called synapses. They allow neurons within the brain to communicate with one another across brain regions, creating a global interconnected neural network within each individual person. At a molecular level, synapses are highly complex. Their protein composition that fine-tunes their function is immensely variable, producing high synaptic diversity within the brain. This diversity is thought to be the underlying origin of cognitive processes, with different behaviours arising from different patterns of brain activity – known as the connectionist model.

The success of the project has the potential to enhance our understanding of human thoughts and behaviour and could pinpoint where it all goes wrong in disease.

The Grant group has already had success in creating a mouse synaptome. Using cutting-edge imaging and analysis techniques, they were able to use the synaptome to map the activity of the brain while mice were performing decision-making behaviours. This was the first molecular map at a single synapse level produced for any organism. While this will have a huge impact on our understanding of how our brain works, it also sheds light on what can go wrong in disease. For instance, the group demonstrated a phenomenon which they called ‘synaptome reprogramming’. 

Synaptic reprogramming is described as an adaptive response causing changes in the distribution of synapses in response to mutations affecting proteins found at synaptic interfaces. Such mutations have knock-on effects on the ability of synapses to relay signals to connected neurons. The researchers explored this mechanism in mouse models of autism spectrum disorder (ASD) and schizophrenia. It was discovered that the disease-causing mutations resulted in altered communication between synapses with widespread effects across the brain, causing alterations to patterns of brain activity associated with certain behaviours. These changes are thought to represent the symptoms experienced by patients, such as the sensory dysfunction present in ASD or the hallucinations affecting schizophrenia sufferers. This opens up countless new applications for this tool, including the growing challenge of dementia and the complications associated with ageing. Being able to predict changes to the synaptome in diseases associated with dementias such as Alzheimer’s and Amytrophic Lateral Sclerosis (ALS) could aid with enhancing new treatments and discovering new mechanisms of both normal and diseased brain function.

By continuing this work to develop a human synaptome, the Grant group is providing an invaluable proof-of-concept. Firstly, by validating the findings in the mouse synaptome, and secondly, by creating a freely available tool which could allow the exploration of the effects of disease-causing mutations of neural communication. 

The paper detailing the mouse synaptome work can be found in Neuron at:

This article was written by Ayisha Mahmood and edited by Tara Wagner-Gamble

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