RT Journal Article SR Electronic T1 Altered synaptic adaptation and gain in sensory circuits of the casein kinase 1 delta (CK1dT44A) mouse model of migraine JF bioRxiv FD Cold Spring Harbor Laboratory SP 719039 DO 10.1101/719039 A1 Pratyush Suryavanshi A1 Punam Sawant Pokam A1 KC Brennan YR 2019 UL http://biorxiv.org/content/early/2019/07/30/719039.abstract AB Migraine is a very common and disabling neurological disorder that remains poorly understood at the cellular and circuit level. Transgenic mice harboring a mutation in casein kinase 1 delta (CK1dT44A) represent the first animal model of non-hemiplegic migraine. These mice have decreased sensory thresholds to mechanical and thermal pain after treatment with the migraine trigger nitroglycerin; and an increased susceptibility to cortical spreading depression (CSD), which models the migraine aura. In this study, we investigated cellular and synaptic mechanisms within sensory cortical circuits that might underlie the migraine relevant phenotypes of CK1dT44A mice, using in vitro and in vivo whole cell electrophysiology. Surprisingly we found that at resting state, CK1dT44A neurons exhibited hyperpolarized membrane potentials, due to increased tonic inhibition. Despite this reduction in baseline excitability, CK1dT44A neurons fired action potentials more frequently in response to current injection. And despite similar synaptic and dendritic characteristics to wild type neurons, excitatory but not inhibitory CK1dT44A synapses failed to adapt to high frequency short-stimulus trains, resulting in elevated steady state excitatory currents. The increased steady state currents were attributable to an increased replenishment rate of the readily releasable pool, providing a presynaptic mechanism for the CK1dT44A phenotype. Finally, during in vivo experiments, CK1dT44A animals showed increased duration and membrane potential variance at ‘cortical up states’, showing that the intrinsic and synaptic changes we observed have excitatory consequences at the local network level. In conclusion excitatory sensory cortical neurons and networks in CK1dT44A animals appear to exhibit decreased adaptation and increased gain that may inform the migraine phenotype.