Keywords
1. Zebrafish Brain Development
2. PCDH19
3. Functional Connectomics
4. Multiplane Calcium Imaging
5. Network Topology Disruption
A recent groundbreaking study published in eNeuro has unveiled significant insights into how functional brain networks self-assemble during development and the underlying molecular basis of these processes. The paper titled “Multiplane Calcium Imaging Reveals Disrupted Development of Network Topology in Zebrafish pcdh19” dives into the developmental phases of the zebrafish brain and the role of Protocadherin-19 (PCDH19) in orchestrating network topology—fundamental in understanding a variety of neurodevelopmental disorders.
Using sophisticated multiplane calcium imaging technology, researchers from the Ohio State University, primarily Sarah E. W. Light and James D. Jontes, closely observed zebrafish mutants lacking proper PCDH19 function. The study, supported in part by the National Institutes of Health (NIH) under grant R01 EY027003, has made remarkable strides in mapping these developmental aspects in vivo, which has historically been a challenging endeavor.
Protocadherins, including PCDH19, are a subset of the cadherin superfamily—a group of molecules known for their cell-adhesion properties, necessary for various cell interactions and signal transductions that dictate tissue and organ formation. PCDH19, in particular, has been implicated in troubling neurodevelopmental abnormalities when mutations are present.
The study DOI is 10.1523/ENEURO.0420-18.2019, and its full citation is as follows:
Light, S. E. W., & Jontes, J. D. (2019). Multiplane Calcium Imaging Reveals Disrupted Development of Network Topology in Zebrafish pcdh19. eNeuro, 6(3), ENEURO.0420-18.2019. https://doi.org/10.1523/ENEURO.0420-18.2019
The experiment focused on capturing the real-time activities within the brain using transgenically modified zebrafish whose neurons expressed ultrasensitive calcium indicators (Chen et al., 2013). Calcium imaging is a revered tool because of its ability to monitor the electrical activity of neurons, as the ions play a key role in transmitting signals in the nervous system (Jercog et al., 2016).
Disruption in the normal development of network topology was observed in the pcdh19-mutant zebrafish. Control groups of normal functioning pcdh19 genes showed a natural progression towards more complex and interconnected neural networks, which are essential for advanced brain functions and behaviors. This contrasted starkly with specimens exhibiting PCDH19 dysfunction, where the resultant neural networks appeared less intricate and more chaotic, failing to stabilize into functional patterns.
The importance of the PCDH19 gene in early neural network formation endorses the hypothesis that certain neurodevelopmental disorders, especially those that preferentially affect females such as PCDH19-related epilepsy, have a fundamental cellular connectivity issue (Depienne et al., 2009). This breakthrough opens up new avenues for research into the therapeutic targeting of neurodevelopmental and connectomic disorders including, but not limited to, schizophrenia and autism (Fornito et al., 2016; Collin et al., 2016).
References
1. Light, S. E. W., & Jontes, J. D. (2019). Multiplane Calcium Imaging Reveals Disrupted Development of Network Topology in Zebrafish pcdh19. eNeuro, 6(3), ENEURO.0420-18.2019. https://doi.org/10.1523/ENEURO.0420-18.2019
2. Chen, T. W., et al. (2013). Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature, 499(7458), 295–300. https://doi.org/10.1038/nature12354
3. Depienne, C., et al. (2009). Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet, 5(2), e1000381. https://doi.org/10.1371/journal.pgen.1000381
4. Fornito, A., Zalesky, A., & Bullmore, E. (2016). Fundamentals of brain network analysis. London, UK: Academic Press.
5. Collin, G., Turk, E., & van den Heuvel, M. P. (2016). Connectomics in schizophrenia: from early pioneers to recent brain network findings. Biol Psychiatry Cogn Neurosci Neuroimaging, 1(3), 199–208. https://doi.org/10.1016/j.bpsc.2016.01.002
6. Jercog, P., Rogerson, T., & Schnitzer, M. J. (2016). Large-scale fluorescence calcium-imaging methods for studies of long-term memory in behaving mammals. Cold Spring Harb Perspect Biol, 8(12), a021824. https://doi.org/10.1101/cshperspect.a021824
Through such meticulous research, the biological and neurological community gains essential insight into the intricate processes that shape our very ability to function and perceive the world. Moreover, studies like these emphasize the value of model organisms, such as zebrafish, in uncovering the complexities of human brain development and dysfunction. This could provide clinicians, scientists, and researchers with a more precise diagnostic lens and a stronger platform for treatment strategies tailored to individual genetic backgrounds and developmental profiles.
It’s imperative that ongoing and future research initiatives take inspiration from this study to delve deeper into the less-charted waters of neural development. Understanding how network topology can go awry promises not only advances in biomedical sciences but also hope for patients and families affected by a spectrum of developmental and neurological conditions.