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People use cannabidiol (CBD), the primary non-psychoactive cannabinoid of cannabis, as a treatment for symptoms that are commonly associated with pregnancy including nausea, pain, and anxiety. Many people believe CBD is safe to take during pregnancy. However, CBD crosses the placenta and affects the activity of protein targets that are expressed in the fetal brain. Cannabidiol alters the activity of ion channels including voltage- gated sodium, potassium, and calcium channels that control the electrical activity of neurons. Abnormal electrical activity could disrupt brain function via changes in axon growth and synapse structure and function. Furthermore, CBD alters the activity of G- protein coupled receptors that are expressed in the fetal brain and are important for axon growth and guidance suggesting that fetal exposure could prevent axons from reaching their correct targets. Indeed, cannabidiol exposure reduces axon growth in vitro and in vivo. This raises the possibility that CBD consumption during pregnancy could disrupt fetal brain development. Recent studies show that oral cannabidiol consumption during pregnancy alters the excitability of the pyramidal neurons of the prefrontal cortex and affects postnatal cognitive function in mouse offspring. Furthermore, fetal CBD exposure increases thermal pain sensitivity in offspring. Gestational cannabidiol exposure affects compulsivity and memory in a different rodent model. Here, we discuss how CBD affects various ion channels and G-protein coupled receptors, the roles of these proteins in neurodevelopment, and evidence that CBD affects brain development.
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l-Isoaspartyl Methyltransferase Deficiency in Zebrafish Leads to Impaired Calcium Signaling in the Brain
Isomerization of l -aspartyl and l -asparaginyl residues to l -isoaspartyl residues is one type of protein damage that can occur under physiological conditions and leads to conformational changes, loss of function, and enhanced protein degradation. Protein l -isoaspartyl methyltransferase (PCMT) is a repair enzyme whose action initiates the reconversion of abnormal l -isoaspartyl residues to normal l -aspartyl residues in proteins. Many lines of evidence support a crucial role for PCMT in the brain, but the mechanisms involved remain poorly understood. Here, we investigated PCMT activity and function in zebrafish, a vertebrate model that is particularly well-suited to analyze brain function using a variety of techniques. We characterized the expression products of the zebrafish PCMT homologous genes pcmt and pcmtl . Both zebrafish proteins showed a robust l -isoaspartyl methyltransferase activity and highest mRNA transcript levels were found in brain and testes. Zebrafish morphant larvae with a knockdown in both the pcmt and pcmtl genes showed pronounced morphological abnormalities, decreased survival, and increased isoaspartyl levels. Interestingly, we identified a profound perturbation of brain calcium homeostasis in these morphants. An abnormal calcium response upon ATP stimulation was also observed in mouse hippocampal HT22 cells knocked out for Pcmt1 . This work shows that zebrafish is a promising model to unravel further facets of PCMT function and demonstrates, for the first time in vivo , that PCMT plays a pivotal role in the regulation of calcium fluxes.
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- Award ID(s):
- 1714569
- PAR ID:
- 10249419
- Date Published:
- Journal Name:
- Frontiers in Genetics
- Volume:
- 11
- ISSN:
- 1664-8021
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fgene.2020.612343
