Human Neurons Differ From Animal Ones in a Surprising WayIn a surprising new finding published in Nature, neuroscientists have shown that human neurons have a much smaller number of ion channels than expected, compared to the neurons of other mammals.
Ion channels are integral membrane proteins that contain pathways through which ions can flow. By shifting between closed and open conformational states (‘gating’ process), they control passive ion flow through the plasma membrane.
The researchers hypothesise that lower channel density may have helped the human brain evolve energy efficiency, letting it divert resources elsewhere.
“If the brain can save energy by reducing the density of ion channels, it can spend that energy on other neuronal or circuit processes,” said senior author Mark Harnett, an associate professor of brain and cognitive sciences.
Analysing neurons from 10 different mammals, the researchers identified a “building plan” that holds true for every examined species — save humans. They found that as the size of neurons increases, the density of channels found in the neurons also increases.
However, human neurons proved to be a striking exception to this rule.
“Previous comparative studies established that the human brain is built like other mammalian brains, so we were surprised to find strong evidence that human neurons are special,” said lead author and former MIT graduate student Lou Beaulieu-Laroche.
Neurons in the mammalian brain can receive electrical signals from thousands of other cells, and that input determines whether or not they will fire an electrical impulse called an action potential. In 2018, Prof Harnett and Beaulieu-Laroche discovered that human and rat neurons differ in some of their electrical properties, primarily in dendrites.
One of the findings from that study was that human neurons had a lower density of ion channels than neurons in the rat brain. The researchers were surprised by this observation, as ion channel density was generally assumed to be constant across species. In their new study, Harnett and Beaulieu-Laroche decided to compare neurons from several different mammalian species to see if they could find any patterns that governed the expression of ion channels. They studied two types of voltage-gated potassium channels and the HCN channel, which conducts both potassium and sodium, in layer 5 pyramidal neurons, a type of excitatory neurons found in the brain’s cortex.
They were able to obtain brain tissue from a range of 10 mammalian species, including human tissue removed from patients with epilepsy during brain surgery. This variety allowed the researchers to cover a range of cortical thicknesses and neuron sizes across the mammalian kingdom.
In nearly every mammalian species the researchers examined, the density of ion channels increased as the size of the neurons went up. Human neurons bucked this trend, having a much lower density of ion channels than expected.
The increase in channel density across species was a surprise, Prof Harnett explained, because the more channels there are, the more energy is required to pump ions in and out of the cell. However, it started to make sense once the researchers began thinking about the number of channels in the overall volume of the cortex, he said.
In the tiny brain of the Etruscan shrew, which is packed with very small neurons, there are more neurons in a given volume of tissue than in the same volume of tissue from the rabbit brain, which has much larger neurons. But because the rabbit neurons have a higher density of ion channels, the density of channels in a given volume of tissue is the same in both species, or any of the nonhuman species the researchers analysed.
“This building plan is consistent across nine different mammalian species,” Prof Harnett said. “What it looks like the cortex is trying to do is keep the numbers of ion channels per unit volume the same across all the species. This means that for a given volume of cortex, the energetic cost is the same, at least for ion channels.”
The human brain represents a striking deviation from this building plan, however. Instead of increased density of ion channels, the researchers found a dramatic decrease in the expected density of ion channels for a given volume of brain tissue.
The researchers believe this lower density may have evolved as a way to expend less energy on pumping ions, which allows the brain to use that energy for something else, like creating more complicated synaptic connections between neurons or firing action potentials at a higher rate.
“We think that humans have evolved out of this building plan that was previously restricting the size of cortex, and they figured out a way to become more energetically efficient, so you spend less ATP per volume compared to other species,” Prof Harnett said.
He now hopes to study where that extra energy might be going, and whether there are specific gene mutations that help neurons of the human cortex achieve this high efficiency. The researchers are also interested in exploring whether primate species that are more closely related to humans show similar decreases in ion channel density.
