Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• GABAergic inhibitory interneurons are crucial for brain circuit function.
• Primary cilia are increasingly recognized for their roles in neuronal development and function.
• The specific role of primary cilia in interneuron development and synaptic integration remains unclear.

Purpose of the Study:

• To investigate the role of primary cilia, specifically the GTPase Arl13b, in GABAergic interneuron development and function.
• To determine the impact of disrupted primary cilia on interneuron morphology, synaptic connectivity, and network activity.
• To explore potential rescue mechanisms involving G-protein-coupled receptor (GPCR) signaling within primary cilia.

Main Methods:

• Generated conditional knockout mice with selective loss of Arl13b in interneurons.
• Utilized chemogenetics to manipulate ciliary GPCR signaling.
• Assessed interneuron morphology, synaptic connectivity, and excitatory/inhibitory balance using electrophysiology and imaging techniques.

Main Results:

• Loss of Arl13b in interneurons disrupted primary cilia, leading to impaired interneuron morphology and synaptic integration.
• These structural deficits resulted in an altered excitatory/inhibitory activity balance in neural circuits.
• Chemogenetic activation of ciliary GPCR signaling or re-expression of Sstr3 in mutant cilia rescued the observed deficits.

Conclusions:

• Primary cilia, through Arl13b and GPCR signaling, are essential for proper interneuron development and synaptic connectivity.
• Disruption of ciliary function leads to functional imbalances in inhibitory neural circuits.
• Targeting primary cilia-mediated GPCR signaling offers a potential therapeutic avenue for disorders involving inhibitory circuit dysfunction.