Early Career Investigator Commentary
Biological Psychiatry
Links Between Patterns of Embryonic Spinal Cord Development and Schizophrenia Risk Emily L. Casanova The entry point of the spermatozoon dictates the placement of the animal pole and thus the dorsoventral axis of the early embryo, eliminating the once-radial symmetry of the egg. Radial symmetry is further broken by the primitive streak, demarcating the left–right and rostral–caudal axes. This newfound bilateral symmetry is short-lived, however, disturbed by development of the (generally) right-sided loop formation of the heart tube and subsequent asymmetrically placed organ systems, such as the liver, spleen, and digestive tract (1). The halves of the central nervous system are paired, providing rough mirror images of one another across a bilateral axis, but specific compartments also develop asymmetrically and are functionally lateralized in humans (2–4). Probably the best studied of these are the cerebral hemispheres concerning the lateralization of language, handedness, and aspects of visuospatial reasoning. While visuospatial attention, for instance, is predominantly lateralized to the right hemisphere, language is almost invariably lateralized to the left, with occasional exceptions (4,5). Interestingly, early postnatal maturation of the left cerebral hemisphere is delayed compared to that of the right, particularly within the ventral superior temporal sulcus, a region that is intimately involved in language, suggesting that rates of asymmetric development may share general links with functional specialization (2). Most fibers of the corticospinal tract decussate at the level of the medulla oblongata, crossing to the contralateral side of the spinal cord to synapse onto motoneurons and communicate with the peripheral nervous system, regulating motor movements on the opposite side of the body. Like language, handedness is typically lateralized to the left cerebral hemisphere in humans, with about 90% of the population reporting a right-handed preference (6). There has been much research on the topic of handedness, but until now, our understanding of the prenatal underpinnings of motor preference has left important questions unanswered. In this issue of Biological Psychiatry, de Kovel et al. (7) shed new light on a novel aspect of handedness in humans. Unlike most research that has centered around the cerebral cortex, the team focused on early development of the fetal spinal cord. de Kovel et al. found that, similar to the development of the left cerebral hemisphere, maturation of the right side of the 4- to 8-week-old fetal spinal cord is transcriptionally delayed compared to its mirror half, exhibiting functional enrichment patterns centered around cell division and proliferation. Meanwhile, the transcriptome of the left, more advanced side of the spinal cord exhibits patterns related to cell differentiation, such as glutamate receptor signaling and neurotransmitter transport. The team concluded that because this asymmetry
develops before decussation of the corticospinal tract, which occurs no earlier than 8 weeks after conception, neocortical tissue does not drive spinal cord asymmetries in a top-down manner, but that these asymmetries are at least partly tissue autonomous. Likewise, they report that the fetal midbrain during this period exhibits maturational delays ipsilateral to those of the cerebrum and contralateral to the spinal cord, reflecting its position superior to the pyramidal decussation within the medulla. According to the researchers, however, transcriptional asymmetry within the midbrain is muted compared to that measured within the spinal cord. Previous studies have reported increased rates of lefthandedness in the schizophrenic population. However, some have considered this a gender artifact caused by the male-skewed sex ratio in the condition and higher rates of left-handedness among men in general. Performing a meta-analysis, however, Hirnstein and Hugdahl (8) reaffirm this risk pattern, suggesting that prevalence rates of lefthandedness in schizophrenia probably hover around 15%. Like left-handedness, altered cerebral asymmetry has been reported in schizophrenia, albeit less consistently (9). For these reasons, the etiology of hemispheric lateralization has been an ongoing focus of schizophrenia research. de Kovel et al. (7) went on to determine whether schizophrenia-associated polymorphisms significantly overlap the transcriptomes of specific stages of spinal cord development, using single nucleotide polymorphisms from the Psychiatric Genomics Consortium. They found that schizophrenia single nucleotide polymorphisms targeted genes whose transcripts were asymmetrically expressed in fetal spinal cord, while the same was not seen in fetal midbrain. What’s more, genes whose expressions changed most strongly over this developmental period, which were preferentially expressed in the developmentally advanced (left) side of the spinal cord, likewise strongly overlapped schizophrenia risk genes. This suggests that genes expressed within more mature differentiated cells share stronger links with schizophrenia risk. These results suggest that schizophrenia risk is associated with genes expressed during particular developmental periods, not necessarily those that are preferentially lateralized. de Kovel et al. studied 149 genes that showed consistent asymmetries in expression and, once more, found that leftlateralized genes overlapped risk genes, indicating that prenatal disturbances to lateralization may well underlie aspects of schizophrenia risk. de Kovel et al. (7) concluded that early spinal cord lateralization may influence cerebral asymmetries that arise in later development. However, high rates of leftward
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http://dx.doi.org/10.1016/j.biopsych.2017.05.006 ISSN: 0006-3223
& 2017 Society of Biological Psychiatry. e21 Biological Psychiatry August 1, 2017; 82:e21–e22 www.sobp.org/journal
Biological Psychiatry
Commentary
lateralization of language and its association with motoric dominance may indicate otherwise. If so, one might expect language to be consistently lateralized to the right hemisphere in left-handed people, which is infrequently the case (4). Instead, morphogenetic signals common to both the cortex and spinal cord may be responsible for paired deviations in the pathology of schizophrenia—especially when one considers that most risk genes, such as those involved in neurotransmission, are not specific to spinal cord but are present throughout the central nervous system (10). Therefore, if the expression or functionality of gene products key to schizophrenia risk is impaired, one would expect both the brain and the spinal cord to be affected. However, the likelihood that patterns of spinal cord development reinforce those seen within the cortex is great, considering the role neural activity plays in patterning neurite connectivity. Yet whether changes to spinal cord connectivity are capable of significantly remodeling hemispheric dominance to any considerable extent remains to be seen. Lesion studies suggest that possibility. While this study undoubtedly reinforces the ongoing interest into lateralization by the schizophrenia research community, bringing deserved light to a region of the central nervous system—the spinal cord, all too ignored in neurodevelopmental disorder research—it only scratches the surface of the potential role, if any, the spinal cord could play in schizophrenia risk. Additional studies addressing the spinal cord’s role in influencing cerebral lateralization are warranted in order to determine the extent that neural activity versus tissue autonomous factors drive cerebral lateralization. In addition, in the case of schizophrenia, it is imperative that we learn whether altered laterality is a risk factor for the condition, or whether it is simply a secondary symptom—the result of a common etiology. Might that etiology be better described as the result of impairments to cellular maturation as de Kovel et al.’s (7) results would likewise support? Additional research will continue to address these important questions.
mentored by a senior investigator. This work was mentored by Manuel Casanova, M.D. This work was supported by National Institutes of Health Grant No. R01 HD-65279. I would like to thank Dr. Manuel Casanova for his help in reviewing and editing this manuscript. This article would not have been possible without his help. The author reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Department of Biomedical Sciences, University of South Carolina Medical School at Greenville, Greenville, South Carolina. Address correspondence to Emily L. Casanova, Ph.D., University of South Carolina, Patewood Medical Campus, 200A Patewood Drive, Greenville, SC 29615; E-mail:
[email protected]; ecasanova@ghs. org. Received May 2, 2017; accepted May 3, 2017.
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Acknowledgments and Disclosures Early Career Investigator Commentaries are solicited in partnership with the Education Committee of the Society of Biological Psychiatry. As part of the educational mission of the Society, all authors of such commentaries are
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