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 alpha1 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.
Title: Choline acetyltransferase and acetylcholinesterase containing projections from the basal forebrain to the amygdaloid complex of the rat Emson PC, Paxinos G, Le Gal la Salle G, Ben-Ari Y, Silver A Ref: Brain Research, 165:271, 1979 : PubMed
The origin of the cholinergic innervation to the amygdaloid complex was investigated with the use of acetylcholinesterase (AChE) histochemistry and choline acetyltransferase (ChAT) assay of microdissected nuclei. Visualization of AChE-positive neurones in the ventral forebrain was facilitated by pretreatment of rats with 1.5 mg/kg di-isopropyl phosphofluoridate (DFP). The AChE-positive neurones in the ventral forebrain are distributed in a continuous system from the septum through the lateral preoptic area to the entopeduncular nucleus caudally. Knife cuts or kainic acid injections (1.5 microgram/l microliter) placed in the lateral preoptic area resulted in substantial depletion of the AChE and ChAT content of the amygdala nuclei. Kainic acid injections (1.5 microgram/l microliter) in the diagonal band area or cuts through the stria terminalis dorsally did not significantly modify the AChE staining or ChAT content of the amygdala (although diagonal band injections partially depleted the hippocampus of ChAT). Knife cuts severing both the so-called ventral pathway and the stria terminalis did not produce significantly greater ChAT depletion in the amygdala than those produced by the knife cuts or kainic acid injections in the lateral preoptic area. Parasagittal knife cuts undercutting the lateral pyriform cortex also failed to modify the AChE or ChAT content of the amygdala, but they depleted the undercut cortex of both ChAT and AChE; AChE-positive material accumulated ventrally and medially to the knife cut. It is suggested that the major source of the cholinergic innervation of the amygdala is the magnocellular AChE-positive neurones in the lateral preoptic area and adjacent regions of the ventral forebrain.
Title: Species variation in the distribution of cholinesterases in the ovary of the plains viscacha, cat, ferret, rabbit, rat, guinea-pig and roe deer Silver A Ref: Histochemical Journal, 10:79, 1978 : PubMed
Sections of ovary from plains viscacha, cat, ferret, rabbit, rat, guinea-pig and roe deer have been histochemically processed to demonstrate acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in nervous and non-nervous tissue. The effects of different reproductive states on enzyme activity were observed in some animals. AChE-containing nerves were sparse in rabbit and rat but plentiful in cat and roe deer. Nerves containing BuChE were not detectable in ferret or guinea-pig and were rare in cat. Species variations in the activity and type of enzyme were also found in non-neuronal tissues. Some blood vessels in the ovaries of guinea-pig and viscacha contained AChE. No other species showed a reaction for AChE in non-neuronal stromal tissue but BuChE was present at this site in all animals except rat. Granulosa cells reacted for AChE only in cat and rabbit while luteal cells were reactive in cat, rabbit and roe deer. Some BuChE activity was present in granulosa and or luteal cells in all species except roe deer. In rat, BuChE activity in luteal cells increased during pregnancy and the early phase of pseudopregnancy. The difficulty of assigning a function to ovarian cholinesterases is discussed.
Title: Acetylcholinesterase in blood vessels of the guinea-pig ovary during different phases of the reproductive cycle Silver A Ref: Histochemical Journal, 9:341, 1977 : PubMed
The distribution of acetylcholinesterase-containing blood vessels in the ovary has been investigated histochemically during the reproductive cycle of the guinea-pig. Whole mounts as well as frozen sections have been studied. Stained vessels were found in the stroma throughout the oestrous cycle and pregnancy. In the corpus luteum the vascular reaction varied at different stages of the oestrous cycle; while never very pronounced, it was more marked in lactating than in non-lactating animals. A feregnancy advanced an increasing number of vessels were strongly stained. At the end of pregnancy, stained vessels were less prominent. Acetylcholinesterase appeared to be localized prinicipally in the vessels themselves (possibly in muscle cells) rather than in associated nerves. Experiments in which ovaries were injected, via their arterial or venous supply, with starch or coloured gelatine suggested that most stained vessels were arterioles but a reaction also occurred in some vessels which were probably arteries and others which could have been the postulated arterio-venous shunts. Capillaries were unstained; whether the veins were also totally unreactive could not be established. The significance of the changes in acetylcholinesterase staining in varying functional states remains obscure; they may or may not reflect the emergence of certain types of vessel at different stages.
Title: Cholinesterase activity in the corpus luteum of the sheep and pig Silver A Ref: Indian Journal of Physiology & Pharmacology, 21:295, 1977 : PubMed
The acetylcholinesterase (AHhE) activity in the corpora lutea of ovaries from sheep has been examined at different stages of pregnancy and the oestrous cycle, by both quantitative and histochemical techniques. The enzyme activity rose during the early part of pregnancy and then levelled out; it appeared to fall sharply at term. During the oestrous cycle the AChE activity was much lower but showed time-related changes. A few results from pigs and cows are included. The cows corpora lutea, unlike those of the sheep and pig contained butyrylcholinesterase (BCHE) as well as AChE. The results are discussed in terms of the possible function of non-neuronal cholinesterases.
Title: Acetylcholinesterase activity in blood vessels of the guinea-pig ovary [proceedings] Silver A Ref: The Journal of Physiology, 263:101P, 1976 : PubMed
Title: Proceedings: Cholinesterase activity in the autotransplanted ovary of a sheep Harrison FA, Heap RB, Silver A Ref: The Journal of Physiology, 242:10P, 1974 : PubMed
Title: Proceedings: Histochemical localization of acetylcholinesterase-containing nerve fibres in the testis Langford GA, Silver A Ref: The Journal of Physiology, 242:9P, 1974 : PubMed
Title: The effect of a hemisection on the distribution of acetylcholinesterase and choline acetyltransferase in the spinal cord of the cat Gwyn DG, Wolstencroft JH, Silver A Ref: Brain Research, 47:289, 1972 : PubMed
Title: The distribution of cholinesterases in relation to the structure of the spinal cord in the cat Silver A, Wolstencroft JH Ref: Brain Research, 34:205, 1971 : PubMed
Title: Histochemical demonstration of acetylcholinesterase in the hypothalamus of the female guinea-pig Cottle MK, Silver A Ref: Z Zellforsch Mikrosk Anat, 103:570, 1970 : PubMed
Title: Cholinesterases and choline acetylase in the spinal cord of the cat Silver A, Wolstencroft JH Ref: The Journal of Physiology, 210:92P, 1970 : PubMed
Title: An investigation of the nerve supply to thealt gland of the duck Ash RW, Pearce JW, Silver A Ref: Q J Exp Physiol Cogn Med Sci, 54:281, 1969 : PubMed
Title: The correlation between choline acetyltransferase and acetylcholinesterase activity in different areas of the cerebellum of rat and guinea pig Kasa P, Silver A Ref: Journal of Neurochemistry, 16:386, 1969 : PubMed
Title: The histochemical demonstration of acetylcholinesterase in the hypothalamus of the female guinea-pig Cottle MK, Silver A Ref: The Journal of Physiology, 198:63passim, 1968 : PubMed
Title: Confirmation from choline acetylase analyses of a massive cholinergic innervation to the rat hippocampus Lewis PR, Shute CC, Silver A Ref: The Journal of Physiology, 191:215, 1967 : PubMed
Title: Cholinesterases of the central nervous system with special reference to the cerebellum Silver A Ref: International Review of Neurobiology, 10:57, 1967 : PubMed
Title: Acetylcholine and choline acetyltransferase in the diaphragm of the rat Hebb CO, Krnjevic K, Silver A Ref: Journal of Physiology, 171:504, 1964 : PubMed
Title: Confirmation from choline acetylase analyses of a massive cholinergie innervation to the hippocampus Lewis PR, Shute CCD, Silver A Ref: Journal of Physiology London, 172:9, 1964 : PubMed
Title: The Effect of Denervation on Sweat Glands and Meissner Corpuscles of Human Hands Silver A, Montagna W, Versaci A Ref: Journal of Investigative Dermatology, 42:307, 1964 : PubMed
Title: The spontaneous release of acetylchofine from the denervated hemidiaphragm of the rat Mitchell JF, Silver A Ref: Journal of Physiology London, 165:117, 1963 : PubMed
Title: A Histochemical Investigation of Cholinesterases at Neuromuscular Junctions in Mammalian and Avian Muscle Silver A Ref: The Journal of Physiology, 169:386, 1963 : PubMed
Title: Choline acetylase in the central nervous system of man and some other mammals Hebb CO, Silver A Ref: Journal of Physiology, 134:718, 1956 : PubMed
Title: A histochemical study of cholinesterases of rabbit retina and optic nerve Hebb CO, Silver A, Swan AA, Walsh EG Ref: Q J Exp Physiol Cogn Med Sci, 38:185, 1953 : PubMed
