AIS plasticity

What is the axon initial segment (AIS) and what are its main functions?

The AIS is a specialised region at the beginning of the axon that:

• Integrates synaptic potentials

• Is the main site of action potential initiation

• Helps maintain cell polarity by acting as a boundary that separates somatodendritic proteins from axonal proteins preventing the somatodendritic proteins from incorrectly entering the axon

• Contains a very high density of voltage-gated ion channels (high density of NaV channels).

Why is the AIS the main site of action potential initiation?

It contains a very high density of voltage-gated Na⁺ (NaV) channels — around 5–50× somatic levels — making it highly sensitive to depolarisation.

What scaffolding proteins identify and organise the AIS?

AnkyrinG (AnkG) + βIV-spectrin, which form a complex that anchors ion channels to the axonal membrane.

What is the role of KV1 channels at the AIS?

They help shape the action potential waveform and occur at around 10× the density found elsewhere.

Does the AIS always begin directly from the soma?

No. The AIS is always located on the axon, but the axon itself can originate:

• Proximally from the soma

• Distally from the soma

• From a dendrite.

Why are neurons with axon-carrying dendrites more excitable?

Their AIS:

• Has a more hyperpolarised AP threshold so it needs less depol to generate an AP

• Is closer to synaptic input so less filtering and signal from dendrite will not weaken as it travels

• Is less affected by somatic inhibition. AIS gets inhibitory inputs but ACS doesn’t

Which NaV channel subtype is especially abundant at the AIS?

NaV1.6.

AIS NaV channels also have lower activation/inactivation thresholds than somatic NaV channels.

What are the different roles of NaV1.6 and NaV1.2 at the AIS?

NaV1.6

• More distal

• Lower activation threshold

• More important for AP initiation

NaV1.2

• More proximal

• More important for back-propagating APs into the somatodendritic region.

What is AIS plasticity?

Structural and/or functional changes to the AIS that alter AP initiation and neuronal excitability.

When is AIS plasticity recruited?

In response to chronic changes in neural activity, helping counteract periods of abnormally high or low activity and keep activity within a safe/normal range.

Why is AIS plasticity considered homeostatic?

Because it tends to oppose prolonged changes in neuronal activity:

Too much activity → AIS changes to ↓ excitability

Too little activity → AIS changes to ↑ excitability

This helps stabilise neural activity.

What happens to the AIS when neurons are chronically depolarised with KCl and how does this affect neuronal activity?

15 mM KCl for 48 h → chronic depolarisation so increased activity but because of potassium imbalance inside and outside the cells just stop firing completely→ AIS shifts distally (away from soma).

Makes AP initiation more difficult by reducing neuronal excitability as signal must now travel further and will weaken to get to the AIS

What channels act as activity sensors for AIS plasticity?

L-type and T-type Ca²⁺ channels.

Blocking these channels prevents AIS plasticity.

Can optogenetic stimulation induce AIS plasticity?

Yes, but only stimulation patterns mimicking physiological neural activity induced AIS plasticity.

How are neurons organised in the avian cochlear nucleus?

How does AIS length differ between high- and low-frequency auditory neurons?

Tonotopically:

• High-frequency neurons → rostral-medial

• Low-frequency neurons → caudal-lateral.

Low-frequency cells have longer AISs so more NaV channels hence greater excitability than high-frequency cells.

What happens to NaV channels during AIS development?

NaV channel density increases, along with changes in which NaV subtypes are prevalent.

What did otocyst lesion experiments reveal about developmental AIS plasticity?

Did sensory deprivation prevent NaV channel accumulation during development?

Removing sensory input prevented the normal tonotopic differences in AIS length, showing that activity contributes to AIS development.

No. Lesions did not prevent NaV channel accumulation or normal changes in subtype prevalence.

AIS development is only partly activity-dependent:

• AIS length differences → activity-dependent

• NaV accumulation/subtype changes → not fully activity-dependent.

therefore, developmental AIS plasticity is only partially activity dependent

What happens to AIS length when sensory input is reduced by whisker trimming?

Why does AIS length increase/decrease following sensory deprivation?

Sensory deprivation causes a reversible increase in AIS length in the whisker-barrel cortex.

Reduced sensory activity → neuron compensates by increasing AIS length → increases excitability, helping restore activity.

Need to be trimming minimum 15 days before seeing changes in AIS which means that for 15 days the mice cannot sense food, water etc which is needed for survival

What is the effect of environmental enrichment (EE) on neural activity?

What is the effect on AIS plasticity and how long does this last?

EE provides novel sensory stimulation → increases sensory/neural activity.

Increased neuronal activity→ shorter AIS → decreased excitability

The effect does not work for long periods and when returned back to the normal environment, AIS length returns to normal

What happens to the AIS when NMDA receptors are activated?

NMDA receptor activation:

→ shortens AIS length

→ increases AP voltage threshold

→ makes the neuron less excitable.

Why are short-term AIS changes likely functional?

AIS lengthening requires new NaV channels to be transported, which takes time. So rapid AIS changes likely alter existing ion-channel function, not AIS structure.