A defining feature of the brain is the ability of its synaptic contacts to adapt structurally and functionally in an experience-dependent manner. In the human cortex, however, direct experimental evidence for coordinated structural and functional synaptic adaptation is currently lacking. 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. These synaptic adaptations were accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and required mRNA translation. It was not observed in synaptopodin-deficient mice, which lack spine apparatus organelles. We conclude that atRA is a potent mediator of synaptic plasticity in the adult human cortex.
Keywords: human; human cortex; mouse; neuroscience; retinoic acid; synaptic plasticity; synaptopodin; vitamine A.
The brain has an enormous capacity to adapt to its environment. This ability to continuously learn and form new memories thanks to its malleability, is known as brain plasticity. 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. These sites of synaptic contact occur through microscopic protrusions on the branches of neurons, called dendritic spines. Dendritic spines are very dynamic, changing their shape and size in response to stimuli. 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 the rodent brain. Recently, a derivative of vitamin A has been linked to synaptic plasticity. In addition, several studies have evaluated the effects of this derivative in patients with cognitive dysfunctions, including Alzheimer’s disease, Fragile X syndrome, and depression. However, there is no direct experimental evidence for synaptic plasticity in the adult human cerebral cortex related to vitamin A signaling and metabolism. To investigate this, Lenz et al. used human cortical slices prepared from neurosurgical resections and treated them with a solution of the vitamin A derivative all-trans retinoic acid for 6-10 hours. Lenz et al. employed a variety of techniques, including patch-clamp recordings to measure neuron function as well as different types of microscopy to evaluate structural changes in dendritic spines. These experiments demonstrated that the derivative promoted the synaptic plasticity in the adult human cortex. Specifically, it increased the size of the dendritic spines and strengthened their ability to transmit signals. In addition, Lenz et al. found that the spine apparatus organelle – a structure found in some dendritic spines – was a target of the vitamin A derivative and promoted synaptic plasticity. These findings advance the understanding of the pathways through which vitamin A derivatives affect synaptic plasticity, which may aide the development of new therapeutic strategies for brain diseases. More generally, the results contribute to the identification of key mechanisms of synaptic plasticity in the adult human brain.
© 2021, Lenz et al.