Sustained inhibitory dysfunction in complement component C1qa-deficient mice underlies epilepsy and comorbidities.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Neuronal network refinement is crucial for brain function.
• Complement component C1qa (C1qa) dysregulation is linked to neurological disorders, primarily affecting excitatory synapses.
• The role of C1qa in inhibitory circuits is poorly understood.

Purpose of the Study:

• Investigate the impact of C1qa downregulation on inhibitory circuits.
• Determine C1qa's role in somatostatin (SST)-expressing interneurons in the somatosensory cortex.
• Elucidate C1qa's contribution to neurological dysfunction and absence seizures.

Main Methods:

• Germline deletion of C1qa in a mouse model.
• Analysis of layer 6 SST interneurons in the somatosensory cortex.
• Electrophysiological recordings to assess synaptic transmission and network activity.
• Behavioral tests for anxiety and sensory-driven responses.
• Transplantation of medial ganglionic eminence (MGE)-derived interneuron precursors.

Main Results:

• C1qa deletion disrupts layer 6 SST interneurons.
• This disruption leads to enhanced excitatory synaptic transmission and electrographic spike-and-wave discharges.
• Mice exhibited anxiety-like behavior and impaired sensory-driven behavior.
• Interneuron precursor transplantation rescued behavioral deficits but not the seizure phenotype.

Conclusions:

• C1qa is critical for maintaining inhibitory network integrity.
• C1qa downregulation contributes to neurological disorders through interneuron dysfunction.
• Additional mechanisms beyond interneuron dysfunction are involved in absence seizure pathophysiology.