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.

Pei-Fen Siow,Chwen-Yu Chen,Li-Jen Lee,I-Shing Yu,Ho-Ching Chang,Chih-Yu Tsao,Kuang-Yung Lee

doi:10.3390/ijms21144921

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.

Highlights

Seizures are the result of neuronal hyperactivity that causes involuntary behavioral changes, such as twitching of the limbs, while epilepsy is a chronic condition characterized by repetitive seizures and is one of the most common neurological disorders [1]
We examined the reactions of FbCtgf KO mice in a PTZ-induced seizure model
We demonstrated, the first time, the PTZ-induced seizures and cellular responses in mice lacking Ctgf in the forebrain structures, including the dorsal endopiriform nucleus (DEPN)

Summary

Introduction

Seizures are the result of neuronal hyperactivity that causes involuntary behavioral changes, such as twitching of the limbs, while epilepsy is a chronic condition characterized by repetitive seizures and is one of the most common neurological disorders [1]. 30% of patients do not respond well to the first-line anticonvulsants. Many of these patients require a combination of anticonvulsants but such treatments are still unable to effectively stop seizure recurrence [1,2]. There is an urgent need for patients, clinicians and researchers to identify new drug targets and develop effective therapies. To achieve this goal, investigation of underlying mechanisms using mouse models in the field of experimental medicine is indispensable for successful drug development [3,4,5]

Methods

Results

Conclusion