Abstract

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications that characterize migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. This is partly due to the paucity of genetic animal models associated with the common, less severe form of the disease. A mutation in casein kinase 1 delta (CK1{delta}) was identified in familial migraine with aura and advanced sleep phase syndrome. Spreading depolarization (SD), the phenomenon that underlies migraine aura, is facilitated in mice carrying one of the mutations (CK1{delta}T44A). However, the mechanism of this susceptibility is not known. We used a combination of whole-cell electrophysiology and imaging, in vivo and in ex vivo brain slices, to understand the cellular and synaptic underpinnings of this apparent circuit excitability. We found that despite normal synaptic activity and hyperpolarized neuronal membrane potentials at rest, CK1{delta}T44A neurons were more excitable upon repetitive stimulation compared to wild-type (WT) controls. This was due to reduced presynaptic adaptation to high-frequency stimuli at excitatory, but not inhibitory synapses. Reduced adaptation at glutamatergic CK1{delta}T44A synapses was mediated by a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles. This caused an increase in the cumulative amplitude of excitatory currents, and a higher excitation-to-inhibition ratio during sustained activity, both in vivo and in brain slices. Fluorescence imaging revealed increased glutamate release in CK1{delta}T44A compared to WT brain slices, corroborating the presynaptic gain of function observed with electrophysiology. Action potential bursts elicited in individual CK1{delta}T44A neurons enhanced glutamatergic feedback excitation within local microcircuits, further amplifying firing frequencies. At a network level in vivo, CK1{delta}T44A mice showed increased duration of up state activity, which is dependent on recurrent excitation. Finally, we demonstrated that SD susceptibility of CK1{delta}T44A brain slices could be returned to WT levels with the same reductions in extracellular calcium that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased SD susceptibility and may also explain the sensory amplifications that are associated with the disease.