Activity-dependent regulation of synaptic strength and cellular mechanisms of migraine

点击翻译按钮获取中文摘要

Migraine is a chronic neurological disorder where affected patients experience recurrent attacks of moderate to severe headaches that are often accompanied by other debilitating symptoms such as nausea, vomiting and sensitivity to light, smell, or sound. Migraine affects over 10% of the population and represents a major disease burden for society. The neuronal mechanisms of this syndrome remain however poorly understood.Some inherited cases of migraine, as well as other episodic neurological disorders such as ataxia (incoordination due to abnormal cerebellar function) and epilepsy, are caused by mutations of ion channels that gate calcium, sodium, or potassium fluxes across presynaptic membranes during action potentials. These "presynaptic neurological channelopathies" are thought to destabilise neuronal networks by affecting the release of neurotransmitters. The effects of the disease mutations on the channel functions in channelopathies can be precisely determined by electrophysiological methods. Therefore, understanding the mechanisms of channelopathies provides invaluable insights into the pathogenesis of more common forms of migraine, ataxia and epilepsy.The conventional way to study channelopathies is to determine the precise effects of a mutation at the single channel level and then to relate these effects to changes in synaptic transmission in neuronal models of disease. However, this straightforward approach often leads to paradoxical results. Using our pilot data we hypothesise that the missing key to understanding these diseases is homeostatic compensation of synaptic transmission, which, although abundantly documented in experimental studies, has been largely overlooked in studies of pathogenic mechanisms. Homeostatic synaptic plasticity is a negative feedback mechanism, which compensates for increases or decreases in neuronal activity by adjusting the strengths of innervating synapses. Our preliminary data argue that channelopathies do invoke homeostatic changes. Furthermore, an understanding of homeostatic compensation could go a long way to resolve the long-standing puzzle why most neurological channelopathies are episodic disorders, which generally do not interfere with brain function between manifestations of the disease.In this project we propose for the first time to systematically study the role of homeostatic mechanisms in channelopathies using mouse models of Familial Hemiplegic Migraine Type 1 (FHM1). FHM1 is caused by mutations in the CACNA1A gene that encodes the pore forming subunit of P/Q-type presynaptic calcium channels that are the major triggers of neurotransmitter release in the brain. We have recently developed a set of new imaging methods, which allow us to study the relationship between calcium entry and vesicular exocytosis, and to probe presynaptic ion channel function in individual small presynaptic terminals. Using these techniques we will determine to what extent the gain of function effects of two different FHM1 CACNA1A mutations (S218L and R192Q) are homeostatically compensated in different types of brain neuronal networks. This should provide first insights into the role and the limitations of homeostatic compensation for inherited ion channel dysfunction, which can be used as a novel framework to understanding the abnormal behaviour of neuronal circuits in paroxysmal neurological disorders. In a long term our results may identify new target mechanisms to prevent or mitigate the clinical manifestations of intermittent disturbances of synaptic transmission.