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There are tens of billions of neurons in the brain, the vast majority of which are excitatory. In this context, it is remarkable that the brain is not more prone to hyperexcitability, with seizures arising only in very specific conditions. However, despite decades of effort, why seizures occur when they do remains poorly understood. We are thus interested in how the neurochemical environment and different cell types regulate brain excitability. For this, we employ electrophysiology combined with multisite photometry, Miniscope and two-photon microscopy in ex vivo and in vivo mouse models of paroxysmal disorders.

The role of neurotransmitters and neuromodulators in controlling brain excitability

Patients’ propensity to experiencing seizures changes throughout the day and is influenced by brain states. Therefore, seizure susceptibility not only depends on predictable circadian rhythms, but also on stochastic brain states. Key regulators of neuronal excitability, namely neurotransmitters (NTs) and neuromodulators (NMs), are strongly modulated by circadian rhythms and brain states and so by tracking their fluctuations we aim to better understand and predict seizure occurrence. 
Here we use genetically-encoded neurotransmitter indicators and multi-site fiber photometry to monitor the major NTs/NMs in chronic models of epilepsy. 


Dual fibre photometry in acute model of epilepsy (PTZ). A. GCaMP6 activity in the insular cortex and CA1 region of the hippocampus during seizures. B. GCaMP6 activity in the visual cortex and CA1 region. Note that for both recordings CA1 is only activated during seizures. (Images modified from Biorender) 

Cellular origin of hyperexcitability in epilepsy

Here, we use a combination of electrocorticogram recordings and either two-photon imaging or miniaturized microscope (Miniscope), combined with cell-type specific expression of GCaMP6, to monitor the activity of different cell types during experimentally induced or spontaneous seizures in head-fixed and freely behaving animals. In addition, we use closed-loop optogenetic stimulation and chemogenetic manipulation to assess the necessity and sufficiency of the different neuron classes to promote / suppress seizures.  

Here are two of our current projects: 
1. The role of dysplatic neurons in seizure generation associated with Focal Cortical Dysplasia
2. Harnessing slow dendritic inhibition to prevent seizure generation in temporal lobe epilepsy

Miniscope imaging in FCD animals. (A) GCaMP6 expression in RhebCA- neurons and (B) in RhebCA+ neurons. (C) FCD animal wearing miniscope. (D) Miniscope field of view (FOV, left), fluorescence signals in 31 cells (middle) and correlation matrix (right). (E) single cell fluorescence signals from 14 neurons and widefield signal from the FOV in (D) before, during and after a behavioural seizure. Note that the signal saturated after the seizure due to cortical spreading depolarization. (F) Simultaneous electrocorticogram (ECoG) and single-cell calcium imaging during PTZ induced seizures. 

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