Autism and Action potential back-propagation: a story about sodium channels distributions
What causes autism? How does a tiny mutation in sodium channel's structure vastly increase the likelihood of developing autism? How do voltage dynamics in the dendrites effect learning, and how is the signal generated in the axon felt in the dendrites? All of these questions are answered in a new study about how mutations in the voltage gated sodium channel Nav1.2 can contribute to autism. Genetic studies of people with autism have revealed that mutations that diminish Nav1.2 currents result in a significant increase in the chance of developing autism. This mutation weakens action potential generation, and diminishes the action potential backpropagation into the dendrites. This has a direct effect on how a cell learns, and as a result people with a mutant version of Nav1.2 channels are at a very high risk of developing autism. This study was published in the paper The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex, the authors Perry W.E.Spratt, RoyBen-Shalom, Caroline M.Keeshen, Kenneth J.BurkeJr. Rebecca L.Clarkson, Stephan J.Sanders, and Kevin J.Bender.
Recall that all neurons fire action potentials. This is because when the voltage reaches a certain threshold, sodium channels open and sodium rushes into the cell. This will cause the voltage to increase, until the higher voltage opens potassium channels (and deactivates the sodium channels) causing the voltage to drop. This causes the stereotypical action potential. However there are many types of voltage gated sodium channels. In the axon there are at least two types of sodium channels that are commonly found. Nav 1.6 is found throughout the axon and this is the sodium channel most responsible for generating and propagating the action potential. Initially, Nav 1.2 is found primarily in the axon during development. However as the organism develops and ages, Nav 1.2 is restricted to the axon initiation segment (AIS). This region, sometimes called the axon hillock, is a region of dense sodium channel concentration that is important is initiating the action potential. However, because Nav1.2 current is diminished the strength of the action potential is much smaller. While this does not affect the all-or-no action potential down the axon it does greatly affect the action potential backpropagation.
Under normal conditions a large voltage depolarization can be felt in the dendrites. This is because the voltage will diffuse away from the AIS into the dendrites, attenuating as it propagates backwards into the dendrites. Proximal regions of the dendritic tree will have a stronger response, while distal regions will feel a smaller voltage response. While this attenuation is constant between the mutant neurons and normal neurons, the initial action potential is weaker in the mutant. Less sodium current into the neuron, means that the depolarization amplitude of the action potential is weaker. Thus when the authors measure the voltage in the dendritic tree, they measure a weaker signal than they would expect in a healthy cell.
To explain why this action potential back-propagation is so important, it's useful to think about how synapses work. As I have said before. NMDA receptors only open when the voltage is high and there is plenty of glutamate neurotransmitter in the synaptic cleft. One of the reasons that the voltage near the NMDA receptors might be high, is because the action potential back-propagation into the dendrites and caused the voltage to increase. This is important, because NMDA lets calcium into the cell, and this can set of a calcium signalling cascade that is important in synaptic plasticity and Hebbian learning. Recall, Hebbian learning is the implementation of the phrase, “Neurons that fire together, wire together.” If a synapse receiving input is correlated with the neuron firing, its strength is increased. Thus, if action potential back-propagation is negatively affected then synapses will have a hard time “knowing” if they cause the cell to fire, making the up-regulation of the synaptic weight hard. Therefore, deficits in Nav1.2 channels can hurt synaptic excitability and make it difficult for the neuron to learn. Thus because the cell has a harder time learning, the likelihood of developing autism is higher.
Author: Alexander White
Source: Perry W.E.Spratt, RoyBen-Shalom, Caroline M.Keeshen, Kenneth J.BurkeJr. Rebecca L.Clarkson, Stephan J.Sanders, and Kevin J.Bender. The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex, Neuron, 2019. 103(4), Pages 673-685.e5
https://www.sciencedirect.com/science/article/pii/S0896627319304908
Recall that all neurons fire action potentials. This is because when the voltage reaches a certain threshold, sodium channels open and sodium rushes into the cell. This will cause the voltage to increase, until the higher voltage opens potassium channels (and deactivates the sodium channels) causing the voltage to drop. This causes the stereotypical action potential. However there are many types of voltage gated sodium channels. In the axon there are at least two types of sodium channels that are commonly found. Nav 1.6 is found throughout the axon and this is the sodium channel most responsible for generating and propagating the action potential. Initially, Nav 1.2 is found primarily in the axon during development. However as the organism develops and ages, Nav 1.2 is restricted to the axon initiation segment (AIS). This region, sometimes called the axon hillock, is a region of dense sodium channel concentration that is important is initiating the action potential. However, because Nav1.2 current is diminished the strength of the action potential is much smaller. While this does not affect the all-or-no action potential down the axon it does greatly affect the action potential backpropagation.
Under normal conditions a large voltage depolarization can be felt in the dendrites. This is because the voltage will diffuse away from the AIS into the dendrites, attenuating as it propagates backwards into the dendrites. Proximal regions of the dendritic tree will have a stronger response, while distal regions will feel a smaller voltage response. While this attenuation is constant between the mutant neurons and normal neurons, the initial action potential is weaker in the mutant. Less sodium current into the neuron, means that the depolarization amplitude of the action potential is weaker. Thus when the authors measure the voltage in the dendritic tree, they measure a weaker signal than they would expect in a healthy cell.
To explain why this action potential back-propagation is so important, it's useful to think about how synapses work. As I have said before. NMDA receptors only open when the voltage is high and there is plenty of glutamate neurotransmitter in the synaptic cleft. One of the reasons that the voltage near the NMDA receptors might be high, is because the action potential back-propagation into the dendrites and caused the voltage to increase. This is important, because NMDA lets calcium into the cell, and this can set of a calcium signalling cascade that is important in synaptic plasticity and Hebbian learning. Recall, Hebbian learning is the implementation of the phrase, “Neurons that fire together, wire together.” If a synapse receiving input is correlated with the neuron firing, its strength is increased. Thus, if action potential back-propagation is negatively affected then synapses will have a hard time “knowing” if they cause the cell to fire, making the up-regulation of the synaptic weight hard. Therefore, deficits in Nav1.2 channels can hurt synaptic excitability and make it difficult for the neuron to learn. Thus because the cell has a harder time learning, the likelihood of developing autism is higher.
Author: Alexander White
Source: Perry W.E.Spratt, RoyBen-Shalom, Caroline M.Keeshen, Kenneth J.BurkeJr. Rebecca L.Clarkson, Stephan J.Sanders, and Kevin J.Bender. The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex, Neuron, 2019. 103(4), Pages 673-685.e5
https://www.sciencedirect.com/science/article/pii/S0896627319304908
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