Concussive Head Trauma Deranges Axon Initial Segment Function in Axotomized and Intact Layer 5 Pyramidal Neurons.

Area of Science:

• Neuroscience
• Cell Biology

Background:

• The axon initial segment (AIS) is crucial for action potential (AP) generation and neuronal signaling.
• Neocortical axonal injury, common in traumatic brain injury (TBI), often occurs at the AIS, potentially disrupting its specialized function.

Purpose of the Study:

• To investigate how concussive TBI affects the functional specialization of the AIS.
• To identify the cellular mechanisms underlying AIS dysfunction post-TBI.

Main Methods:

• High-resolution recordings of APs from layer 5 pyramidal neurons in Thy1-YFP-H mice one and two days after mild central fluid percussion injury.
• Second derivative (2°) analysis to quantify AIS- and soma-regional contributions to the AP upstroke.
• Assessment of AIS morphology and excitability, including ankyrin-G staining.

Main Results:

• A subset of axotomized neurons showed an abolished AIS-regional 2° peak, indicating functional perturbation, diminished excitability, and AIS distention.
• Another subpopulation exhibited merged AIS- and soma-regional 2° peaks, suggesting altered sodium channel function or AIS initiation zone translocation.
• Knockout of cyclophilin-D ameliorated these effects, implicating mitochondrial calcium dysregulation.

Conclusions:

• Concussive TBI causes significant functional and structural perturbations of the AIS.
• Mitochondrial calcium dysregulation is a key factor in trauma-induced AIS dysfunction.
• These findings highlight the AIS as a vulnerable site in TBI and suggest potential therapeutic targets.