Clustered Protocadherins Are Required for Building Functional Neural Circuits

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal identity relies on cell-surface clustered protocadherin (Pcdh) isoforms.
• 58 Pcdh isoforms from α, β, and γ gene clusters are differentially expressed in mouse neurons.
• Pcdh isoforms mediate synapse specificity through homophilic interactions.

Purpose of the Study:

• To investigate the role of clustered Pcdh isoforms in postnatal neural circuit development.
• To overcome neonatal lethality in clustered-Pcdh-null mice for developmental analysis.

Main Methods:

• Generation of chimeric mice with transplanted clustered-Pcdh-null (Δαβγ) neurons.
• Generation of double mutant mice (Δαβγ/Bax null) to prevent Pcdh-null neuronal loss.
• Calcium imaging of cultured hippocampal neurons.
• Analysis of trans-homophilic interactions of Pcdh-γA3 isoforms.

Main Results:

• Chimeric mice with high Δαβγ cell contribution showed paralysis and postnatal death.
• Δαβγ neurons in the forebrain were spared from apoptosis, unlike brainstem neurons.
• Δαβγ/Bax null mutants exhibited a non-alternating central pattern generator for locomotion.
• Cultured Δαβγ neurons displayed synchronized network activity and reduced variability.
• Trans-homophilic interactions require a complete match of Pcdh isoform repertoires.

Conclusions:

• Combinations of clustered Pcdh isoforms are essential for constructing functional neural circuits.
• Pcdh isoforms play critical roles in neuronal survival, synapse formation, and network activity.
• Isoform-specific trans-homophilic interactions are crucial for precise neural connectivity.