Using electron microscopy images, the researchers visualize the dendritic spines (yellow) with their spine apparatus (red) and the synapse terminal buttons (blue).[Andreas Vlachos]

Brain plasticity, also known as neuroplasticity, is a term that refers to the brain’s ability to change and adapt as a result of experience. A person’s brain is constantly changing and adapting to environmental stimuli. One of the most important mechanisms behind brain plasticity is the change in both the structure and function of synapses, the points of contact between neurons where communication happens. At birth, each neuron in the cerebral cortex has approximately 2,500 synapses. By the time an infant is two or three years old, the number of synapses is approximately 15,000 synapses per neuron.

Previous studies have shown that alterations in synaptic plasticity occur in various animal models of brain diseases. However, it remains unclear whether human cortical neurons express synaptic plasticity similarly to those in mice.

“Physicians have long suspected that remodeling processes also take place in humans at the contact points between nerve cells, i.e., directly at the synapses. Until now, however, such a coordinated adaptation of structure and function could only be demonstrated in animal experiments,” explained Andreas Vlachos, PhD, professor from the Institute of Anatomy and Cell Biology at the University of Freiburg. Vlachos and a team of researchers have now provided experimental evidence for synaptic plasticity in humans.

Their findings are published in the journal eLife in a paper titled, “All-trans retinoic acid induces synaptic plasticity in human cortical neurons.”

“A defining feature of the brain is the ability of its synaptic contacts to adapt structurally and functionally in an experience-dependent manner,” wrote the researchers. In the human cortex, however, direct experimental evidence for coordinated structural and functional synaptic adaptation is currently lacking.”

The researchers investigated whether dendritic spines—a small membranous protrusion from a neuron’s dendrite that typically receives input from a single axon at the synapse—would change when exposed to a vitamin A derivative called retionic acid. Dendritic spines play a crucial role in brain plasticity and are constantly adapting to everyday experiences.

“Here, we probed synaptic plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid (atRA), a putative treatment for neuropsychiatric disorders such as Alzheimer’s disease. Our experiments demonstrated that the excitatory synapses of superficial (layer 2/3) pyramidal neurons underwent coordinated structural and functional changes in the presence of atRA,” researchers explained.

The researchers observed retinoic acid not only increased the size of dendritic spines, but also strengthens their ability to transmit signals between neurons.

To prove that synaptic plasticity also exists in humans, the researchers used small samples of human cerebral cortex, which must be compulsorily removed during neurosurgical procedures for therapeutic reasons. They then treated the removed brain tissue with retinoic acid before functional and structural properties of neurons were analyzed using electrophysiological and microscopic techniques.

“We have concluded from our results that retinoic acids are important messengers for synaptic plasticity in the human brain. Thus, this finding contributes to the identification of key mechanisms of synaptic plasticity in the human brain and could support the development of new therapeutic strategies for brain diseases, such as depression,” said Vlachos.

These findings open a door to understanding the pathways through which vitamin A derivatives affect synaptic plasticity. Plasticity plays an important role in the deterioration or alleviation of degenerative brain disorders such as Alzheimer’s and Parkinson’s diseases. These findings may one day lead to the development of new therapeutics for brain diseases affected by plasticity.

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