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Developmental and Post-natal Roles for ERK1/2 Signaling in the Hippocampus

Vithayathil, Joseph

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
The ERK/MAPK pathway is an intracellular signaling pathway that mediates many cellular functions. Mutations in the different elements of this pathway lead to a variety of congenital disorders termed neuro-cardio-facial-cutaneous syndromes (NCFC). These disorders result in many overlapping features including various levels of intellectual disability and cognitive function. In addition, dysregulation of the ERK/MAPK pathway has been implicated in other cognitive and behavioral disorders such as autism, schizophrenia and major depression. Understanding the role of this pathway during development and maturation of the brain will provide critical insight into the pathophysiology of these disorders. The ERK/MAPK pathway has previously been shown to regulate proliferation of neural progenitors during cortical development. Furthermore, pharmacologic studies inhibiting the ERK/MAPK pathway resulted in impaired synaptic plasticity and spatial memory. These studies have identified potential roles for ERK signaling during development and neurophysiologic functions in the hippocampus. The hippocampus is a critical mediator of memory formation and hippocampal volume is altered in various cognitive and behavioral disorders. An important question that remains to be answered is identifying the relative contributions from developmental and post-natal dysregulation of the MAPK pathway in the hippocampus as it relates to the pathophysiology of cognitive deficits observed in NCFC and related syndromes. In examining the development of the hippocampus, we observe that loss of both ERK1 and ERK2 isoforms impairs morphogenesis of the hippocampus resulting in a dentate gyrus that is 1/3 the size of a normal dentate gyrus by post-natal day 10. Furthermore, this phenotype is due to the precocious maturation of radial glial cells and depletion of progenitor populations in the germinal zones that generate the granule cells of the dentate gyrus. Interestingly, the presence of ERK1 is sufficient for normal development of the hippocampus, as knockouts of ERK2 alone do not affect hippocampal morphogenesis. Finally, to examine possible post-natal effects from loss of ERK2 we utilized the developmental ERK2 knockout mice and a post-natal ERK2 knockout mouse to show that the loss of ERK2 does not result in major changes to memory or long-term potentiation in the hippocampus. Interestingly, the post-natal knockout of ERK2 can affect recognition memory and causes delayed spatial learning, but LTP remains intact. These findings show that ERK1 is sufficient for normal development and memory functions of the hippocampus. Furthermore, developmental knockouts of ERK2 appear to perform better than post-natal knockouts of ERK2 in some memory retention tasks suggesting that developmental adaptions from loss of ERK signaling may ameliorate necessity for ERK signaling. These findings highlight the necessity of examining the effects of chronic dysregulation of signaling pathways that regulate hippocampal function, as these phenotypes may be vastly different from phenotypes that are generated from acute inhibition of these pathways.
Evan Deneris, PhD (Committee Chair)
Gary Landreth, PhD (Advisor)
Narla Goutham, MD.PhD (Committee Member)
Friel David, PhD (Committee Member)
Dubyak George, PhD (Committee Member)
237 p.

Recommended Citations

Citations

  • Vithayathil, J. (2015). Developmental and Post-natal Roles for ERK1/2 Signaling in the Hippocampus [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1435760090

    APA Style (7th edition)

  • Vithayathil, Joseph. Developmental and Post-natal Roles for ERK1/2 Signaling in the Hippocampus. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1435760090.

    MLA Style (8th edition)

  • Vithayathil, Joseph. "Developmental and Post-natal Roles for ERK1/2 Signaling in the Hippocampus." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1435760090

    Chicago Manual of Style (17th edition)