Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder

Abstract

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9–25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

The role of selective SATB1 deletion in somatostatin expressing interneurons on endogenous network activity and the transition to epilepsy

“…disturbance and diseases such as epilepsy and neurodevelopmental disorders (Bhat et al, 2014;Lamers et al, 2022;Medina et al, 2022). Close et al (2012) showed that deleting Satb1 from all MGE-derived interneurons at an early developmental stage (using the Dlx5/6 Cre driver line), and thus causing a reduction of their number, led to electrographic interictal discharges during slow-wave sleep (SWS).…”

Response to photic stimulation as a measure of cortical excitability in epilepsy patients

“…Animal studies have indicated that active measures of EEG recordings track cortical excitability in mice [8] add Wei's study if published soon. Perturbing the brain in living humans often involves invasive intracranial surgeries [5; 20; 21; 22; 23], or expensive equipment only accessible to a minority of patient groups such as transcranial magnetic stimulation (TMS), though the perturbation is diffuse and spatially non-specific [6; 7; 24].…”

“…However, delivering perturbations to the brain is generally invasive in practice, requiring implantation of intracranial electrodes or other invasive devices. Animal studies in mice have successfully used electrical stimulation as a perturbation to track cortical excitability [14]. In humans, perturbation studies have used a subset of patients with focal epilepsy eligible for resection surgeries who are undergoing monitoring to confirm the seizure onset zone, where electrodes are placed strategically for that patient’s unique seizure onset zone [15; 16; 17; 18; 19].…”

“…Sensitivity to perturbations can forewarn a state transition [1], therefore biomarkers of the brain's perturbation response or 'cortical excitability' could be used to indicate seizure transitions [2; 3; 4]. However, perturbing the brain often involves invasive intracranial surgeries [5] or expensive equipment as in transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups [6; 7], or animal model studies [8]. Photic stimulation is a widely used diagnostic technique in epilepsy [9] that can be used as a noninvasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans.…”

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy

“…Developmental abnormalities involving the limbic structures, particularly the parahippocampal and entorhinal gyri, likely represent a measurable anatomic consequence of the altered expression of the PCDH19 protein on cortical folding and white matter organization in these anatomic areas [12], and are functionally re ected in the phenotypic features involving neuropsychiatric symptoms, cognitive and communicative skills and local epileptogenesis [3]. Recent studies on animal models have contributed to clarify how PCDH19 mutations alter brain network formation and maintenance [13], and have identi ed mechanisms by which focal mosaic mutations disrupt cortical networks [14] and impair neuronal activity and connectivity [15].…”