The Role Of Excitatory And Inhibitory Activities In Node Recruitment In An Epileptic Network

Background:Epilepsy is a chronic neurological disorder that affects nearly 10 million people in China.Despite the introduction of many new antiepileptic medications,30-40% of all patients with epilepsy continue to have seizures.Although traditional models of epilepsy were based on the concept of an epileptic focus,modern paradigm has been shifted to a re-conceptualization of focal epilepsy as an expression of a large-scale pathologic ‘network’.Focal epilepsy network hypothesis states that epileptiform activity can spread non-contiguously through the brain via highly interconnected nodes,or hubs,within existing networks.Animal models confirming this hypothesis are scarce,and our understanding of how distant nodes are recruited is also lacking.Whether interictal spikes also create and reverberate through a network is not well understood.Objective:Allen Mouse Brain Connectivity Atlas describes monosynaptic connections,to and from sites in the mouse brain.Leveraging the Atlas,we’ll create an in vivo multinodal network mouse model whose epicenter lies within S1 barrel cortex.Using multi-site local field potential(LFP)recording and wide-field mesoscopic imaging of genetically encoded calcium sensors in both pyramidal and PV-interneurons,we will investigate excitatory and inhibitory cell recruitment in mono-and disynaptically connected nodes in an acute model of interictal spikes(IISs).Methods:We injected bicuculline into the S1 barrel cortex and employed multisite local field potential(LFP)and Thy-1 and PV-cell mesoscopic calcium imaging during interictal spikes(IIS)to monitor excitatory and inhibitory cells in two monosynaptically,and one disynaptically connected node: ipsilateral(i)M2,contralateral(c)S1 and c M2.Node participation was analyzed with spike-triggered coactivity maps.Experiments were repeated with 4-aminopyridine as an epileptic agent.Results:We found that each IIS reverberated throughout the network,differentially recruiting both excitatory and inhibitory cells in all connected nodes.The strongest response was found in i M2.Paradoxically,node c M2,which was connected disynaptically to the focus,was recruited more intensely than node c S1,which was connected monosynaptically.The explanation for this effect could be found in nodespecific E/I balance,as c S1 demonstrated greater PV-inhibitory cell activation compared with c M2,where Thy-1 excitatory cells were more heavily recruited.Conclusions:Our data show that interictal spikes spread non-contiguously by exploiting fiber pathways that connect nodes in a distributed network and that excitation/inhibition balance plays a critical role in node recruitment.This multinodal interictal spike network model can be used to investigate cell-specific dynamics in the spatial propagation of epileptiform activity.