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Imaging of synaptic density in the living human brain using the [11C]UCB-J radioactive tracer. Image from Finnema, et al, Sci. Transl. Med. (2016).
Imaging of synaptic density in the living human brain using the [11C]UCB-J radioactive tracer. Image from Finnema, et al, Sci. Transl. Med. (2016).
Imaging of synaptic density in the living human brain using the [11C]UCB-J radioactive tracer. Image from Finnema, et al, Sci. Transl. Med. (2016).

Live imaging of synapse density in the human brain

This article is more than 7 years old

A new imaging technique may give researchers fresh insights into brain development, function, and disease

The human brain is often said to be the most complex object in the known universe, and there’s good reason to believe that it is. That lump of jelly inside your head contains at least 80 billion nerve cells, or neurons, and even more of the non-neuronal cells called glia. Between them, they form hundreds of trillions of precise synaptic connections; but they all have moveable parts, and these connections can change. Neurons can extend and retract their delicate fibres; some types of glial cells can crawl through the brain; and neurons and glia routinely work together to create new connections and eliminate old ones.

These processes begin before we are born, and occur until we die, making the brain a highly dynamic organ that undergoes continuous change throughout life. At any given moment, many millions of them are being modified in one way or another, to reshape the brain’s circuitry in response to our daily experiences. Researchers at Yale University have now developed an imaging technique that enables them to visualise the density of synapses in the living human brain, and offers a promising new way of studying how the organ develops and functions, and also how it deteriorates in various neurological and psychiatric conditions.

The new method, developed in Richard Carson’s lab at Yale’s School of Engineering and Applied Sciences, is based on positron emission tomography (PET), which detects the radiation emitted by radioactive ‘tracers’ that bind to specific proteins or other molecules after being injected into the body. Until now, the density of synapses in the human brain could only be determined by autopsy, using antibodies that bind to and stain specific synaptic proteins, or electron microscopy to examine the fine structure of the tissue.

To get around this, the researchers designed a radioactive tracer molecule called [11C]UCB-J, which binds to a protein called SV2A, which is found exclusively in synaptic vesicles at nerve terminals, and which regulates the release of neurotransmitter molecules from them, a vital step in brain signalling. Other research teams have developed similar tracers that bind SV2A, but so far these have only been tested in rats, pigs and monkeys.

In order to determine that [11C]UCB-J is a reliable marker for synapse density, Carson and his colleagues injected the molecule into an olive baboon and scanned the monkey’s brain. This revealed that the tracer is taken up quickly by the brain tissue, becoming highly concentrated in the cerebral cortex, which consists largely of grey matter densely packed with synapses, but not in white matter tracts, which contains few or no synapses, within 6 to 16 minutes after the injection.

They then dissected the brain and took tissue samples from 12 different regions. Closer examination of these samples using antibody staining further revealed that SV2A levels correspond very closely to those of another protein called synaptophysin, which is considered to be the gold standard of synaptic density, and is used widely to estimate synapse numbers in brain tissue samples. Furthermore, SV2A distribution in the tissue samples was very closely correlated to the measurements obtained earlier by the PET scan, demonstrating that SV2A can be used to accurately measure the density of synapses.

Next, the researchers injected their tracer into five healthy human volunteers, and then scanned their brains, to obtain the very first images of synaptic density in the living human brain. The results were comparable to those seen in the monkey, with the radioactive signal peaking in the grey matter of the cortex within 6 to 15 minutes after injection, and then starting to decline steadily shortly afterwards.

Finally, they repeated this in three patients diagnosed with temporal lobe epilepsy. In all three, the scans showed decreased uptake of the radioactive tracer in the hippocampus, but only on that side of the brain that had previously been damaged by seizures. This not only confirms earlier reports that temporal lobe is associated with the loss of synapses, but also that [11C]UCB-J is sensitive enough to detect it.

Synapses are destroyed in numerous other neurological diseases, including Alzheimer’s, in which the gradual decline of memory function is likely due to loss of synapses in the hippocampus, and major depressive disorder, which is known to involve altered synapse function in the prefrontal cortex. This particular brain region also undergoes extensive synapse loss in adolescence, during which some 40% of the total number of brain synapses are eliminated, a process which we now know continues well into the second decade of life.

Unwanted and damaged synapses are engulfed by microglial cells, the brain’s resident immune cells, in a process called synaptic pruning, and it’s now widely believed that aberrant pruning during early brain development and adolescence could cause, or at least contribute to, conditions such as autism and schizophrenia. (Last year, researchers in London used PET imaging with another radioactive tracer to show that microglial cells are hyperactive in the brains of patients with schizophrenia.)

Refinement of PET imaging using such tracers therefore offers a promising new approach to investigating the changes in synaptic density that occur during brain growth and maturation. It may also provide fresh insights into how diseases that involve synaptic loss develop and progress and, eventually, may even aid in their diagnosis.

Reference

Finnema, S. J., et al. (2016). Imaging synaptic density in the living human brain. Sci. Transl. Med. 8: 348ra96 [Abstract]

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