Transcriptomic mapping uncovers Purkinje neuron plasticity driving learning.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Cellular diversification is essential for brain functions like learning and memory.
• Single-cell RNA sequencing (scRNA-seq) profiles major neuron types, but within-population transcriptomic divergence and functional links are unclear.

Purpose of the Study:

• To profile Purkinje neurons using scRNA-seq and map their responses to motor activity and learning.
• To investigate the functional roles of distinct Purkinje neuron subpopulations in associative learning.

Main Methods:

• Isolation of tagged nuclei from specific cell types followed by single-nucleus RNA sequencing (snRNA-seq).
• In vivo calcium imaging and optogenetic perturbation in mice.
• Weighted gene co-expression network analysis (WGCNA).
• CRISPR-mediated gene knockout of Fgfr2 in Purkinje neurons.

Main Results:

• Two Purkinje neuron subpopulations, Aldoc+ and Plcb4+, were identified with distinct transcriptomic profiles.
• Plcb4+ Purkinje neurons, but not Aldoc+ neurons, showed significant gene expression plasticity during sensorimotor and learning experiences.
• Plcb4+ Purkinje neurons play a critical role in associative learning.
• A learning gene module involving FGFR2 signaling was identified in Plcb4+ neurons.
• FGFR2 knockout in Plcb4+ Purkinje neurons impaired motor learning.

Conclusions:

• Purkinje neuron diversification is linked to motor learning responses.
• Plcb4+ Purkinje neurons are critical for associative learning and motor skill acquisition.
• FGFR2 signaling in Plcb4+ Purkinje neurons is essential for motor learning, offering insights into neurological disorder vulnerability.