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Experts Explore the Role of Neurogenesis in Brain Disorders

Understanding neurogenesis may be the key to understanding and treating some neurological and psychiatric disorders, say scientists in a special issue of Brain Plasticity

November 28, 2018
Amsterdam, NL – Mutations in genes or environmental insults that alter neurogenesis, the growth and development of neurons, are the cause of many neurological and psychiatric disorders. This special issue of Brain Plasticity focuses on the role of neurogenesis in brain disorders.

“The collection of reviews in this issue of Brain Plasticity highlight the basic biology and molecular mechanisms regulating embryonic, postnatal, and adult neurogenesis,” said Guest Editor Bryan W. Luikart, PhD, of the Department of Molecular and Systems Biology, Frank and Myra Weiser Scholar in the Neurosciences, Geisel School of Medicine at Dartmouth, Hanover, NH. “They demonstrate that perturbation of this process at any time in development can directly contribute to many neurological and psychiatric disorders.”

Adult neurogenesis is the process by which new neurons are created from neural stem cells (NSCs) residing in the postnatal brain and is limited to very specific regions within the adult brain. In humans and other mammals, the sub-granular zone (SGZ) of the dentate gyrus (DG) region of the hippocampus is one of only a few brain regions that is capable of generating new neurons throughout the life of the organism. Humans create 700 new neurons per day in the DG, replacing almost two percent of neurons in this region every year. It is likely that this number of cells has a significant impact on brain function and that its process is affected in several neuropsychological and neurodevelopmental diseases.

Patients with major depressive disorders, schizophrenia, addiction, or anxiety disorders exhibit decreased hippocampal volumes. Patients who received treatment with antidepressants have larger DG and granular cell layer volumes. Hippocampal volumes are also smaller in patients with memory disorders. Further targeted molecular studies in mouse models have lent support for disease-related proteins causing changes in adult neurogenesis. These include disease genes for intellectual disabilities such as Rett syndrome and fragile X syndrome.

Xinyu Zhao, PhD, of the Waisman Center and Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, and colleagues review and discuss the regulation of adult neurogenesis by the fragile X family of RNA binding proteins.

“The fragile X mental retardation protein (FMRP) has an important role in neural development,” explained Dr Zhao. “FMRP is part of a larger family of RNA-binding proteins known as FXRs, which also includes fragile X related protein 1 (FXR1P) and fragile X related protein 2 (FXR2P). Functional loss of FMRP in humans leads to fragile X syndrome, and it is the most common monogenetic contributor to intellectual disability and autism.”

Caption: Comparison of human FXR proteins. NTD: N-terminal protein binding domain that contains two agenet domains; NLS: Nuclear localization sequence; KH1 & KH2: RNA-binding domains; NES: Nuclear export sequence; RGG: RNA-binding domain; NoS: Nucleolar localization sequence.

The best-studied FXR in both embryonic and adult neurogenesis is FMRP. Studies in mice showed that the loss of FMRP increased the proliferation capacity of isolated stem cells, which was coupled with an increase in neuronal differentiation. The investigators suggest this may be more pronounced in human cells, but this finding needs further confirmation. FXR1P is not known to directly cause diseases, but protein interactome analysis suggests that FXR1P is highly connected with other autism-related proteins. FXR2P also regulates adult neurogenesis, but its regulatory role seems to be specific to neurogenesis in the DG but not neurogenesis in the subventricular zone. Because FXRs are highly expressed in the brain and are capable of binding thousands of RNA targets, they could be key coordinators of adult neurogenesis. However, the genome-wide identification of FMRP targets has only been done in the mouse forebrain and in human HEK293 cells lines.

“The seemingly small differences between the FXRs lead to individual functions that are just starting to be discovered,” commented Dr. Zhao. “Identification of cell type-specific FXR targets, especially in human NSCs and neurons will be critically important for understanding the function of FXRs in neurogenesis and defining both shared and unique functions of each FXR in neurodevelopment. Understanding the overlapping regulatory functions of FXRs in adult neurogenesis can give us insights into the adult brain and fragile X syndrome.”

Abnormal brain cells in the hippocampus are a defining feature of temporal lobe epilepsy in animals and humans. The significance of these brain cells has long been elusive, however, recent technological advances have begun to reveal that these neurons play a critical role in the development of epilepsy. A review by Steve C. Danzer, PhD, of the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, and Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, OH, describes the key morphological abnormalities exhibited by hippocampal granule cells in epileptic brains, including migration to ectopic locations and disrupted dendritic structure. The development of new technologies to selectively target and manipulate granule cells has led to an acceleration of findings, and new experiments demonstrating that granule cells play a critical role in epileptogenesis (the gradual process by which a normal brain develops epilepsy) are reviewed. Preclinical studies in mouse models indicate that inhibiting or ablating abnormal brain cells in established epilepsy can reduce disease severity. Studies provide proof-of-concept evidence for targeting these neurons to reduce disease burden.

Caption: Images show hippocampal granule cell reconstructions of PTEN-expressing (control) and PTEN knockout (KO) cells from Gli1-CreERT2, PTENfl/fl mice. Cell morphology was revealed by biocytin filling. Cells are projected from above, looking down from the top of the dendritic tree towards the soma. Reconstructions are color-coded by depth. Images reproduced from Santos et al., 2017.

“The development of new technologies in recent years, including cell-type-specific targeting of granule cells in transgenic mouse models, has allowed long-standing hypotheses about the function of these cells to be tested for the first time,” noted Dr. Danzer. “While findings are mixed, and many unanswered questions remain, numerous studies now demonstrate that ablating newborn granule cells can have disease-modifying effects in epilepsy.”

Taken together, these findings provide a strong rationale for continued work to elucidate the role of newborn granule cells in epilepsy, both to understand basic mechanisms underlying the disease and as a potential novel therapy as an alternative to complete hippocampal resection to treat intractable epilepsy.

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NOTES FOR EDITORS
Open Access Special Issue: The Role of Neurogenesis in Brain Disorders
Brain Plasticity, Volume 3, Issue 2
Guest Editor: Bryan W. Luikart, PhD

Featured Articles
Regulation of Adult Neurogenesis by the Fragile X Family of RNA Binding Proteins,” by Natalie E. Patzlaff, Minjie Shen, and Xinyu Zhao (DOI: 10.3233/BPL-170061)
Author contact: Xinyu Zhao (xinyu.zhao@wisc.edu)

Contributions of Adult-Generated Granule Cells to Hippocampal Pathology in Temporal Lobe Epilepsy: A Neuronal Bestiary,” by Steve C. Danzer (DOI: 10.3233/BPL-170056)
Funding for this article was provided by NIH Awards R01NS065020 and R01NS062806.
Author contact: Steve C. Danzer (+1 513-636-4526; steve.danzer@cchmc.org)

Editorial: The Role of Neurogenesis in Brain Disorders,” by Bryan W. Luikart, PhD (DOI: 10.3233/BPL-189001)
Author contact: Bryan W Luikart (+1 603 650 1633; bryan.w.luikart@dartmouth.edu).

This open access issue of Brain Plasticity – Volume 3, Issue 2 (2018)  is available at: content.iospress.com/journals/brain-plasticity/3/2.

Contact
Diana Murray, IOS Press (+1 718-640-5678; d.murray@iospress.com) can be contacted for additional information.

About Brain Plasticity
Brain Plasticity is an open access journal that publishes peer-reviewed original articles, reviews, and short communications on all aspects of neurogenesis, gliogenesis, and synaptic plasticity, from development to the adult. This includes research articles or reviews on modifications to neural circuits in the developing and adult brain, whether by learning or physical activity, spine formation, changes in neural structure, changes in neural networks, new cell division, as well as response of the CNS to experimental injuries, neurodevelopmental and neurodegenerative disorders. Papers adopting fresh conceptual approaches on specification and function at the molecular and cellular levels, neural circuits, systems and behavioral levels are encouraged. iospress.com/brain-plasticity

About IOS Press
IOS Press is headquartered in Amsterdam with satellite offices in the USA, Germany, India and China and serves the information needs of scientific and medical communities worldwide. IOS Press now publishes over 100 international journals and about 75 book titles each year on subjects ranging from computer sciences and mathematics to medicine and the natural sciences. iospress.com