In a surprising new finding, neuroscientists have shown that human neurons have a much lower density of ion channels than expected, compared to the neurons of other mammals. Ion channels produce electrical impulses, which is how neurons communicate. The researchers hypothesize that this reduction in channel density may have helped the human brain evolve to operate more efficiently, allowing it to divert resources to other energy-intensive processes that are required to perform complex cognitive tasks.

The work is published in Nature, in the paper, “Allometric rules for mammalian cortical layer 5 neuron biophysics.”

“If the brain can save energy by reducing the density of ion channels, it can spend that energy on other neuronal or circuit processes,” says Mark Harnett, PhD, associate professor of brain and cognitive sciences at MIT and a member of MIT’s McGovern Institute for Brain Research.

In this study, Harnett and Lou Beaulieu-Laroche, PhD, decided to compare neurons from several different mammalian species to see if they could find 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.

Harnett and colleagues analyzed neurons from ten different mammals: Etruscan shrews (one of the smallest known mammals), gerbils, mice, rats, Guinea pigs, ferrets, rabbits, marmosets, and macaques, as well as 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.the most extensive electrophysiological study of its kind. They found that as the size of neurons increases, the density of channels found in the neurons also increases.

More specifically, they write that, in nine of the ten species, they observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances.

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,” says Beaulieu-Laroche, a former graduate student and lead author on the study.

The increase in channel density across species was surprising, Harnett says, 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 says.

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 analyzed.

“This building plan is consistent across nine different mammalian species,” Harnett says. “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 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,” Harnett says.

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.

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