FGF14 localization and organization of the axon initial segment

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• The axon initial segment (AIS) is critical for action potential initiation, enriched with ankyrin G, βIV-spectrin, and voltage-gated sodium (Nav) channels.
• Previous studies showed Fibroblast Growth Factor 14 (FGF14) is expressed in Purkinje neurons and its inactivation reduces neuronal excitability.

Purpose of the Study:

• To investigate the role and localization of FGF14 within the AIS of Purkinje neurons.
• To examine the impact of altered Nav channel expression on FGF14 and βIV-spectrin distribution.
• To determine how FGF14 deficiency affects AIS protein composition and neuronal excitability.

Main Methods:

• Immunohistochemistry to visualize FGF14, Nav channel subunits (Nav1.1, Nav1.6), βIV-spectrin, and ankyrin G in wild-type, Fgf14(-/-), and Scn8a(med) mouse models.
• Quantitative analysis of protein immunoreactivity and distribution within the Purkinje neuron AIS.

Main Results:

• FGF14 exhibits a proximal-to-distal gradient in the Purkinje neuron AIS, evident during early development.
• In Nav1.6-deficient (Scn8a(med)) mice, FGF14 and Nav1.1 expression are increased, alongside expanded βIV-spectrin.
• FGF14 deficiency (Fgf14(-/-)) leads to modest reductions in Nav1.1 and Nav1.6 in specific AIS sub-domains, without altering ankyrin G or βIV-spectrin levels.

Conclusions:

• FGF14 is a key component of the AIS proteome in Purkinje neurons, with a distinct developmental expression pattern.
• FGF14 levels are inversely correlated with Nav1.6 expression and positively correlated with Nav1.1 expression in the AIS.
• FGF14 influences AIS composition and may contribute to neuronal excitability through modulation of Nav channel function.