Increased presynaptic excitability in a migraine with aura mutation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Migraine is a disabling neurological disorder linked to hyperexcitable sensory circuits, but underlying mechanisms are unclear.
• A mutation in casein kinase 1 delta (CK1δ) is associated with familial migraine with aura and sleep disorders.
• CK1δT44A mutant mice exhibit increased susceptibility to spreading depolarization, the phenomenon underlying migraine aura.

Purpose of the Study:

• To investigate the cellular and circuit-level mechanisms by which the CK1δT44A mutation leads to migraine-relevant phenotypes.
• To elucidate the role of presynaptic adaptation and synaptic vesicle release in the heightened excitability of CK1δT44A neurons.

Main Methods:

• Whole-cell electrophysiology and multiphoton imaging were employed in vivo and in brain slices.
• Comparison of CK1δT44A mutant mice and their wild-type littermates.
• Assessment of synaptic activity, neuronal excitability, vesicle pool dynamics, and network activity.

Main Results:

• CK1δT44A neurons exhibit increased excitability and reduced presynaptic adaptation at excitatory synapses due to enhanced readily releasable vesicle pool.
• This leads to increased glutamate release, higher excitation-to-inhibition ratios, and prolonged 'up state' network activity in mutant mice.
• Reduced extracellular calcium normalized both presynaptic adaptation and spreading depolarization susceptibility in CK1δT44A mice.

Conclusions:

• A stimulus-dependent presynaptic gain of function at glutamatergic synapses occurs in this genetic migraine model.
• This mechanism explains the increased susceptibility to spreading depolarization and potentially the sensory amplifications in migraine.
• Targeting presynaptic function offers a potential therapeutic strategy for migraine.