The Dynamic Coupling Of Neurovascular Unit Under Epileptogenic Process Of Temporal Lobe Epilepsy

Epilepsy is one of common central neurological disorders,characterized of pathological synchronous abnormal firing of neurons,accompanied by repeated seizures.So far,antiepileptic drugs are mainly used to control the symptoms of epileptic seizures.However,current antiepileptic drugs have no effect on the development of epilepsy,and still one third of epilepsy patients have drug resistance.Therefore,it is urgent to probe into the new mechanism of epilepsy development and find effective intervention strategies and drug targets for therapy.Neurovascular coupling,as a basic feature of brain homeostasis,consisted of neuron clusters with their supply vessels,which has been thought to get involved in epilepsy in recent years.However,the dynamic changes of neurovascular units in epilepsy development keeps unknown.In this study,we imaged neurons and vessels in the neurovascular units simultaneously with high spatial and temporal resolution using two-photon microscopy in the epilepsy mice model induced by kainic acid.The parameters of the calcium ion changes in neurons,correlation between capillary blood flow velocity and diameter variation of diving pial vessels were calculated to assess the dynamic change of neurovascular coupling during different phases of epileptogenesis.The results showed that,compared with normal mice,1)During the acute epileptic status,the calcium activity of neurons significantly increased,with blood flow decreased,while the vessel diameter dependently increased or decreased heterogeneously.The changes of calcium ions in neurons were significantly faster than the changes of blood flow and vessel diameter.Besides,correlations between neurons were significantly higher than those between vessels in terms of time-courses.In this period,transient ischemia occurred due to the continuous synchronous activities of neurons,resulting in the depolarization diffuse in the cortex.2)During the process of transition from acute epilepsy to chronic epilepsy,without forefoot electrical stimulation,the changes of neuron calcium ions increased significantly and synchronously,while no significant changes seen in blood flow and vessel diameter.After 21 days,the neurovascular coupling tended to be stable.Under the conditions of forefoot electrical stimulation,the correlation in calcium ions between neurons did not change obviously in response to electric stimulation during chronic epilepsy(0-21 days after acute seizure),but the initial time for blood flow and vessel diameter changing significantly delayed.After 21 days,the attenuation period of neurons to electrical stimulation was significantly shortened,but changes in blood flow and vessel diameter returned to normal state.To summery,by using two-photon imaging to make long-term records during epileptogenensis our study first found that the correlation of neurovascular coupling became nonlinearly gradually compared with normal state,which indicated that the abnormality of neurovascular coupling was involved in the development of temporal lobe epilepsy.The results helped further recognized the role of neurovascular units in the development of temporal lobe epilepsy at micro scale and provided new thoughts for clinical detection and treatment in temporal lobe epilepsy.