Guillemain, I. | Search bioRxiv

bioRxiv2023

How Absence Seizures Impair Sensory Perception: Insights from Awake fMRI and Simulation Studies in Rats

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and- wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in GAERS, a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero-echo-time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.

neuroscience↗

bioRxiv2022

Lack of a key stage of hyper-connectivity between deep and superficial layers during barrel cortex development in a rat model of Absence Epilepsy

The development of cortical neuronal wiring is precisely orchestrated and goes through several stages, some of which coincide with critical periods when sensory experience is most influential. In particular, although ascending excitatory and inhibitory projections from the deep layer 5 to upper layers are first strong, they recede by the end of the critical period of their targets cells located in upper layers. Alterations in these transient innervations impair the construction of the later circuits that remain at adulthood, but it is unknown whether they could lead to pathologies. Here, we address this question in a genetic model of Absence Epilepsy, a neuro-developmental disease, where epileptogenesis occurs during the postnatal maturation of barrel cortex, the seizure initiation site. Using functional mapping by laser scanning photostimulation with glutamate uncaging in slices, we investigated the pattern of projections onto layers 2/3 pyramidal cells from 2-week old rats. We found that its maturation skipped the key stage during which pyramidal cells received strong projections from both excitatory and inhibitory neurons located in deep layers. At the same age, neuronal activity recorded in vivo with two-photon functional imaging was organized in fewer clusters than in control rat pups during this transient hyper-innervation. Later, around the onset of typical absence seizures ([~]1 month old), over-excitability of cells was observed across layers. Using this genetic model of childhood epilepsy, we provide first evidence that failure to develop this transient hyper-innervation from deep cortical layers plays a role in pathological neural dysfunctions. Significance StatementDuring development of cortex, innervation from deep to upper layers is thought to provide a temporary scaffold for the construction of the circuits that remain at adulthood. Whether an alteration in this sequence causes brain malfunctions in neuro-developmental diseases is unknown. Using functional approaches, we investigated in a genetic model of Absence Epilepsy and control rats the maturation of innervation onto layer 2/3 pyramidal cells of barrel cortex and the cell organization into neuronal assemblies. We found that development in this model lacks this early surge of connectivity with deep layers and the concomitant structuring into multiple assemblies. Later on, at seizure onset, neurons in all layers are hyper-excitable, suggesting this feature of epilepsy develops from prior connectivity defects.

neuroscience↗