Skip to main content Skip to secondary navigation
Main content start

Goldilocks and the Three Brains: The Right Amount of Electrical Activity in Neural Development

Figure adapted from Smith et al. Gross anatomical malformations during brain development as a result of expression of mutant SCN3A (right, “Injected”) but not expression of normal SCN3A (left, “Contra”)  

In the brain, neurons depend heavily on electrical currents to carry out their normal functions such as sending signals between neurons. These currents are carried by the flow of various ions into and out of neurons, and need to be well-controlled by ion channels in order to maintain stability [see Chapter 2 in Principles of Neurobiology]. One example of such control is a mechanism called “channel inactivation”, in which an ion channel shuts itself off after a certain amount of time. A classic case of what goes wrong when currents are not controlled is epilepsy [see Box 12-4 in Principles of Neurobiology]. Many inherited epilepsies are caused by inactivation defects in the sodium ion channels that carry positively charged currents into neurons. If these currents are not properly turned off when they should be, neurons and networks of neurons can have runaway excitation, leading to potentially debilitating seizures for patients.

When the embryonic brain is developing, neurons and networks of neurons are often not set up to carry out the communication and computation that occur in the adult brain. There are certainly still currents in many neurons, but instead of primarily being involved in sending signals between neurons, they have a hand in helping the brain get to its mature state. Some examples of processes affected by electrical activity in development are neuronal division, differentiation, migration, survival, and growth. Here, the ion channels controlling the currents again play important roles. In a study by Smith et al at Boston’s Children’s Hospital, we take a closer look at the sodium channel SCN3A and how some altered forms in this protein can lead to disrupted electrical properties in developing neurons and anatomical brain malformations.

The authors began by studying the electrophysiological properties of the SCN3A channel – in other words, they subjected cells with either normal or one of two mutated forms of the channel to various electrical tests and measured their responses. What they found was that while normal versions of this channel inactivated itself after opening for a certain amount of time, both mutated forms may remain more open significantly longer. Interestingly, this didn’t always lead to increases in total amount of current conducted, because some mutated channels allowed a lot less current flow even when they were open. If the ion currents here are important for brain development, then these findings would suggest that proper timing and amount of ion flow are vital parts of the process.

The authors then took one specific mutated form of the SCN3A channel and expressed it in the developing ferret brain, as ferret brains have many of the anatomical and molecular complexities that have been described in human brains. They found that in response to expressing large amounts of the mutated channel, developing ferret brains had disruptions in neuronal migration and brain folding. This corresponds with their observation that the SCN3A channel is normally expressed in human cells that are involved in migration and folding.

One major notable point in this study was that while defects in ion channels often lead to epilepsy, this was not the case for many patients with the mutated forms of SCN3A here. In fact, the currents seen in the developing human neurons with SCN3A often only have small currents, not of the form or magnitude that is involved in communication between mature neurons. This opens up many questions about other roles of electrical activity – how might such small currents affect how cells migrate or develop? What is it about the particular timing or magnitude of current that may be key to normal maturation? These are exciting new questions whose answers may give us insight into how a ball of cells becomes a complex neuronal network throughout neural development.

Reference

R.S. Smith, C.J. Kenny, V. Ganesh, A. Jang, R. Borges-Monroy, J.N. Partlow, R.S. Hill, T. Shin, A.Y. Chen, R.N. Doan, et al. Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development. Neuron, 99 (2018), pp. 905-913.e7. Link