Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Ataxia disorders involve Purkinje cell (PC) dysfunction.
• Reduced BDNF-TrkB signaling contributes to PC dysfunction in spinocerebellar ataxia 6 (SCA6).
• Granule cells (GCs) extensively input to PCs, and their TrkB signaling may impact PC function.

Purpose of the Study:

• Investigate if dysfunctional BDNF-TrkB signaling in a specific subset of cerebellar GCs can cause ataxia.
• Determine if TrkB receptor loss in enkephalinergic precursor-derived GCs leads to motor incoordination.

Main Methods:

• Utilized genetically modified mice lacking the TrkB receptor (encoded by *Ntrk2*) in cerebellar GCs.
• Focused on *Trkb* mice with targeted TrkB receptor deletion in enkephalinergic precursor-derived GCs.
• Assessed cerebellar morphology and synaptic markers alongside behavioral analysis for ataxia symptoms.

Main Results:

• Deleting the *Ntrk2* gene impaired PC function in *Trkb* mice.
• Ataxia symptoms developed in *Trkb* mice.
• Cerebellar morphology and key synaptic markers remained unaffected, indicating signaling dysfunction as the primary cause.

Conclusions:

• Dysfunctional BDNF-TrkB signaling restricted to a subset of cerebellar GCs is sufficient to induce ataxia.
• This pathway may be a contributing factor to motor incoordination in SCA6 and other ataxia disorders.
• Targeting BDNF-TrkB signaling in specific GC populations could be a therapeutic avenue.