Deletion of Phospholipase C β1 in the Thalamic Reticular Nucleus Induces Absence Seizures

Abstract

Absence seizures are caused by abnormal synchronized oscillations in the thalamocortical (TC) circuit, which result in widespread spike-and-wave discharges (SWDs) on electroencephalography (EEG) as well as impairment of consciousness. Thalamic reticular nucleus (TRN) and TC neurons are known to interact dynamically to generate TC circuitry oscillations during SWDs. Clinical studies have suggested the association of Plcβ1 with early-onset epilepsy, including absence seizures. However, the brain regions and circuit mechanisms related to the generation of absence seizures with Plcβ1 deficiency are unknown. In this study, we found that loss of Plcβ1 in mice caused spontaneous complex-type seizures, including convulsive and absence seizures. Importantly, TRN-specific deletion of Plcβ1 led to the development of only spontaneous SWDs, and no other types of seizures were observed. Ex vivo slice patch recording demonstrated that the number of spikes, an intrinsic TRN neuronal property, was significantly reduced in both tonic and burst firing modes in the absence of Plcβ1 . We conclude that the loss of Plcβ1 in the TRN leads to decreased excitability and impairs normal inhibitory neuronal function, thereby disrupting feedforward inhibition of the TC circuitry, which is sufficient to cause hypersynchrony of the TC system and eventually leads to spontaneous absence seizures. Our study not only provides a novel mechanism for the induction of SWDs in Plcβ1 -deficient patients but also offers guidance for the development of diagnostic and therapeutic tools for absence epilepsy.

Corticothalamic Network Abnormalities Underlying Absence Seizures

“…1. genetic ablations of diverse single channel abnormalities in single neuronal populations of the CT network lead to spontaneous ETX-sensitive ASs (Figure 3); CaV2.1 channels in cortical layer 6 neurons (Bomben et al, 2016), CaV2.1 channels in cortical PV+ and SST+ interneurons (Rossignol et al, 2013), NaV1.6 channels in NRT neurons (Makinson et al, 2017), phospholipase C  subunit in NRT neurons (Chang et al, 2022) and phospholipase C 4 subunit in TC neurons (Cheong et al, 2009), whereas selective KD of CaV3.3 channels in NRT neurons does not lead to spontaneous ASs but increases GHB-induced SWDs (Lee et al, 2014); 2. secondary (compensatory) changes in a CT sector other than the one where the primary genetic manipulation had been made may be the critical element for ASs expression indicated by the increased T-type Ca 2+ currents in TC neurons of mice with selective KD of CaV2.1 channels in cortical Layer 6 neurons (Bomben et al, 2016); 3. different changes of membrane proteins expression may occur in diverse areas of CT network, as indicated by the decreased and increased expression of HCN1 channels in the cortex and thalamus, respectively, of WAG/Rij rats (Cain et al, 2015;Kole et al, 2007); 4. in view of the cortical location of SWDs initiation in humans and animal models (see Parts 4 and 5, above), it is unfortunate that almost all investigations that used whole-brain genetic manipulations have studied abnormalities only in thalamic but not cortical neurons, even when the manipulated channels are (highly) expressed in both the cortical and thalamic sectors of CT networks.…”