Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice

Abstract

Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel α1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents.

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats

“…The obvious problem with preclinical migraine research is that it does not mimic the spontaneous onset of migraine. Both pharmacological [23] and genetic [6] approaches have attempted to overcome this disconnect between preclinical models and the human situation. As before, these procedures have been limited because of the inability to continuously monitor migraine pain-related decreases in behavior.…”

Female sex and obesity increase photophobic behavior in mice

“…Photophobia is a key clinical feature of migraine and light avoidance in mice can be a useful tool to evaluate mechanisms underlying migraine-related photophobia (Recober et al, 2009; Recober et al, 2010; Markovics et al, 2011; Kaiser et al, 2012; Chanda et al, 2013). Here we assessed light avoidance in mice as previously described (Rossi et al, 2016), using a modified commercially available apparatus (Med Associates) where mice are given a choice between light and darkness.…”

Chronic ghrelin treatment reduced photophobia and anxiety‐like behaviors in nitroglycerin‐ induced migraine: role of pituitary adenylate cyclase‐activating polypeptide

“…An entry into an open arm was defined as all four paws crossing the center of the maze. After each test, the apparatus was thoroughly cleaned with ethanol 70% (Chanda et al, 2013).…”