The 22q11 microdeletion syndrome is characterized by the age-dependent onset of various psychiatric diseases, including a 30% chance of developing schizophrenia. We have previously discovered an age- dependent increase in long term potentiation (LTP) in the hippocampus of mouse models of 22q11DS. Increased LTP correlates with memory deficits in these mice. Both LTP increase and cognitive deficits become evident in early adulthood. Since the deletion is present in the germ line, it is not clear why these deficits emerge so late in development. The goal of this proposal is to understand the age-dependence of neural deficits in mouse models of 22q11DS. Our recent work showed that the microdeletion gene Dgcr8 is important for increased LTP. Dgcr8 is a double-stranded RNA binding protein important for microRNA biosynthesis. Heterozygous loss of Dgcr8 results in the depletion of specific miRNAs (miR-25 and miR-185) which target the expression of the Sarco/endoplasmic reticular ATPase (Serca2), a protein which pumps Ca2+ into the ER. Reducing these miRNAs results in the increased expression of Serca2 and over-filling of the ER with Ca2+. The resulting alteration in synaptic Ca2+ dynamics is responsible for the observed increase in LTP in Dgcr8+/- mice. Since Dgcr8 and miRNAs are reduced from the beginning of development, however, it is not clear why Serca2 upregulation and LTP deficits appear only in early adulthood. We propose 3 possible mechanisms for age-dependent control of Serca2 expression by miRNAs in these mouse models. First, miRNAs of interest may be normally reduced with age, and the deletion may further deplete them below a phenotypic threshold. Second, the localization of the miRNA-Serca2 pathway may change with development, becoming more important at the synapse with age. Finally, the sensitivity of the Serca2 transcript to these miRNAs may change with age. Several examples of translation that is locally controlled at the synapse now exist in the literature. The packaging of a given transcript in protein and RNA complexes can influence its exposure or sensitivity to miRNAs. Since these 3 mechanisms are not mutually exclusive, one or more of them may be at play in the age-dependence of miRNAs'efef cts on the Serca2 transcript. This study will further clarify a pathway that could be important for the treatment of both 22q11DS and schizophrenia patients. Little is understood about the molecular events important for the development of the human brain during late adolescence and early adulthood, though multiple psychiatric diseases emerge during this period. This proposal outlines a specific study of one molecular pathway that appears to be developmentally regulated and important for disease onset during this stage. Further study of normal and disease development during this critical developmental stage will be the foundation for launching my own laboratory. The career development award would be an important step in establishing this research program.
22q11 deletion syndrome (22q11DS) is the second most common chromosomal disorder after Down syndrome, and involves a range of physical and psychiatric deficits, including a high probability of developing schizophrenia. Understanding neuronal dysfunction in models of 22q11DS is therefore important not only for treating this syndrome, but may also shed light on related psychiatric diseases such as schizophrenia, which affects 1% of the world's population. We have identified a novel molecular pathway that is changed in both 22q11DS and schizophrenia brains, and further study of this pathway could lead to treatments for patients with both diseases.
|Earls, Laurie R; Zakharenko, Stanislav S (2014) A Synaptic Function Approach to Investigating Complex Psychiatric Diseases. Neuroscientist 20:257-71|
|Earls, Laurie R; Westmoreland, Joby J; Zakharenko, Stanislav S (2014) Non-coding RNA regulation of synaptic plasticity and memory: implications for aging. Ageing Res Rev 17:34-42|