Date of Award

2025-05-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Anita M. Quintana

Abstract

Methylmalonic acidemia and homocysteinemia cblX type (cblX) (MIM#309541) is a rare, X-linked recessive disorder caused by a mutation in the HCFC1 gene. This disorder is characterized by multiple congenital anomalies which include intellectual disability, brain malformations, intractable epilepsy, microcephaly, and facial dysmorphia. The most severe symptom of cblX is intractable epilepsy which is 100% penetrant. Our lab developed a zebrafish model with a mutation in the zebrafish hcfc1a ortholog to study the mechanisms underlying seizure phenotypes in cblX. Our laboratory previously showed that mutation of hcfc1a results in increased number and proliferation of neural precursor cells (NPCs) and an increase in AKT/mTOR signaling. Previous studies in the field have confirmed that hyperactivation of mTOR signaling (mammalian target of rapamycin) is associated with seizures. Therefore, we hypothesized that zebrafish with a mutation in hcfc1a are more susceptible to seizures with increased severity relative to their wild-type siblings. To test this, we exposed mutant and wildtype type larvae to pentylenetetrazole (PTZ), a GABA antagonist, with and without inhibition of mTOR. We used Zebrabox technology to record behavioral parameters associated with seizure-like behavior. Suboptimal doses of PTZ did not lead to increased susceptibility in mutant animals, but treatment with mTOR inhibitors was able to reduce the severity of PTZ. We used western blot technology to verify the effects of mTOR inhibition. Our results suggest that hyperactivation of mTOR is partially responsible for seizure severity in hcfc1a mutant larvae but does not enhance seizure susceptibility.

Language

en

Provenance

Received from ProQuest

File Size

45 p.

File Format

application/pdf

Rights Holder

Claudia Berenice Gil

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