Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

Abstract

Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.

Acute and Chronic Neural and Glial Response to Mild Traumatic Brain Injury in the Hippocampus

“…Understanding the cavitation phenomenon will provide better understanding of the causation of these diseases, and therefore may help scientists/engineers develop early detection methodologies, treatments, and prevention measures. This information will elucidate the role of CTGF and TNC in long term brain remodeling, which might be important for understanding the link between TBI and neurodegenerative diseases such as Alzheimer’s Disease and epilepsy( 39–42 ). These findings lay the groundwork for numerous future studies that can utilize this new technique to identify the mechanisms underlying traumatic brain injury and neurodegenerative disease.…”

Enhanced glaucomatous damage accompanied by glial response in a new multifactorial mouse model

“…In a forebrain specific CTGF knock-out model, seizures were induced by pentylenetetrazole. The knock-out mice did not display alterations in microglia number, heterogeneity, or shape ( 105 ). All these results lead to the assumption that the overexpression of CTGF in combination with an immunization increased the microglia response in the model.…”

Is there room in epilepsy for the claustrum?

“…An alternative method to delve into the claustrum's potential involvement in seizures involves measuring its neuronal activity in validated animal models of epileptogenesis. Numerous studies investigating c-fos expression in temporal proximity to SE induced by various methods consistently show increased expression in limbic regions connected to the claustrum such as the hippocampus, piriform cortex, medial prefrontal cortex, entorhinal cortex, amygdala, and anterior nucleus of the thalamus (Morgan et al, 1987;Sitcoske O'Shea et al, 2000;Szyndler et al, 2009;Barros et al, 2015;Siow et al, 2020) (Figure 1B). Studies utilizing kainic acid, pentylenetetrazol, lithium-pilocarpine, and kindling exhibit increased c-fos expression and evidence of neuronal cell death in the claustrum itself (Willoughby et al, 1997;Zhang et al, 1997;Covolan and Mello, 2000;Sitcoske O'Shea et al, 2000;Zhang et al, 2001;Siow et al, 2020;Druga et al, 2024).…”

“…Numerous studies investigating c-fos expression in temporal proximity to SE induced by various methods consistently show increased expression in limbic regions connected to the claustrum such as the hippocampus, piriform cortex, medial prefrontal cortex, entorhinal cortex, amygdala, and anterior nucleus of the thalamus (Morgan et al, 1987;Sitcoske O'Shea et al, 2000;Szyndler et al, 2009;Barros et al, 2015;Siow et al, 2020) (Figure 1B). Studies utilizing kainic acid, pentylenetetrazol, lithium-pilocarpine, and kindling exhibit increased c-fos expression and evidence of neuronal cell death in the claustrum itself (Willoughby et al, 1997;Zhang et al, 1997;Covolan and Mello, 2000;Sitcoske O'Shea et al, 2000;Zhang et al, 2001;Siow et al, 2020;Druga et al, 2024). In fact, a region we recently delineated as being a part of the ventral claustrum in rodents, the dorsal endopiriform nucleus, shows c-fos expression during SE only after the first convulsive seizure, corresponding to the appearance of claustrum sign after the onset of SE in humans (Table 1; Smith et al, 2020;see Majak and Moryś, 2007 for review).…”