HIPPOCAMPAL OVEREXPRESSION OF THE MRNA POLYADENYLATION REGULATOR CPEB4 REDUCES SEIZURE SEVERITY AND CONFERS NEUROPROTECTIVE EFFECTS IN A MOUSE MODEL OF ACUTE SEIZURES

Temporal lobe epilepsy (TLE) is the most common form of epilepsy and causes focal seizures. Epileptogenic insults, such as those seen in TLE, cause large scale disruption to gene expression and gene expression regulation including aberrant polyadenylation profiles which alter translational dynamics via mRNA stability and translational efficiency. Indeed, it is the length of the 3’ poly(A) tail itself which confers important regulatory control. These gene regulatory changes subsequently influence cellular function and behaviour, including seizure susceptibility.
Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA binding protein that regulates mRNA polyadenylation and accumulates in the nucleus of neurons following seizures and other insults. This nuclear accumulation is thought to have neuroprotective effects through increasing the polyadenylation of gene transcripts involved in epilepsy. Indeed, CPEB4 knockout animals suffer more frequent seizures and a more severe seizure phenotype suggesting a protective effect of the protein which this study explores further.
In this study we overexpress CPEB4 using an AAV (Adeno-Associated Virus) in C57 male mice which then undergo intra-amygdala kainic acid (IAKA) injection to provoke status epilepticus. Resulting seizure dynamics were scored and neuropathology was assessed using FluorojadeB staining. CPEB4 overexpression resulted in reduced seizure severity, an increased latency to status epilepticus (SE) onset, and reduced neuronal damage compared to WT mice.
These results demonstrate CPEB4’s neuroprotective and anticonvulsant effect and highlight a potential therapeutic role through alteration of gene expression. Subsequent studies will now explore the anti-epileptogenic potential of CPEB4 targeting as well as the mechanism of neuroprotection.