16 November 2012. Two recent studies in mouse models of 22q11.2 deletion syndrome, a genetic predictor of schizophrenia, reveal mechanisms that could play a role in both illnesses. One study, published November 6 in Proceedings of the National Academy of Sciences, suggests that disrupted migration of parvalbumin neurons is due to lower levels of a chemokine receptor, CXCR4. A second paper, published October 10 in the Journal of Neuroscience, links reduced levels of microRNA DGCR4 to elevations in the calcium ATPase SERCA2 and an increase in hippocampal long-term potentiation in another model of 22q11 deletion syndrome, and also finds increased levels of SERCA2 in postmortem schizophrenia tissue.
22q11 deletion syndrome (22q11 DS), also known as DiGeorge syndrome, knocks out a 1.5 to 3 Mbase span of chromosome 22. This range of deletion lengths is associated with a variable clinical presentation that includes dozens of associated features, including learning impairments, craniofacial abnormalities, and cardiovascular defects. In addition, the genetic syndrome is highly associated with disorders of abnormal cortical circuitry such as autism and schizophrenia (Insel, 2010). In fact, 20-30 percent of 22q11 DS patients develop schizophrenia, and it’s estimated that 1 percent of schizophrenia patients carry the deletion (Bassett and Chow, 2008). Thus, studying 22q11 DS may yield important insights into the pathogenesis of schizophrenia.
Parvalbumin interneurons, 22q11 DS, and schizophrenia
Alterations in GABAergic interneurons and abnormal neuronal migration are hypothesized to play a role in 22q11.2 DS (Mori et al., 2011; Kiehl et al., 2009). Interneuron abnormalities, particularly in cells that express parvalbumin, are also well documented in schizophrenia (see SRF related news story; Fung et al., 2010). In the first study, led by Anthony-Samuel LaMantia of George Washington University in Washington, DC, researchers used the Large Deletion (LgDel) mouse model of 22q11 DS, in which they have previously shown that a redistribution of parvalbumin neurons is present (see SRF related news story), to look for a mechanism underlying this impairment.
In the current study, lead author Daniel Meechan and colleagues also observed a redistribution of parvalbumin neurons, but not other interneuron subtypes, in the LgDel mouse. This altered migration pattern was found to be cell-autonomous, that is, not regulated by the milieu around the cell. A reduction in the mRNA expression levels of several genes known to regulate interneuron migration was also observed. The authors narrowed in on one particular transcript—C-X-C chemokine receptor type 4 (CXCR4)—because it plays a cell-autonomous role in interneuron migration (Stumm et al., 2003).
In addition to lower mRNA levels, protein levels of CXCR4 are also reduced in the LgDel model. When CXCR4 was selectively reduced in LgDel mouse interneurons, the altered migratory phenotype of interneurons was enhanced, leading the authors to suggest that 22q11 DS “is in part a neuronal migration disorder in which diminished … gene dosage disrupts interneuron migration via a CXCR4-dependent mechanism.”
SERCA2, 22q11 DS, and schizophrenia
In a second study, from Stanislav Zakharenko’s lab at St. Jude Children’s Research Hospital in Memphis, Tennessee, researchers investigated a prior observation in a different 22q11 DS mouse model—an age-dependent increase in hippocampal long-term potentiation (LTP) and spatial memory impairment. The increase in LTP is also dependent on an elevation in SERCA2 (Earls et al., 2010), an ATPase that maintains calcium levels in the endoplasmic reticulum. By upregulating calcium levels in the cytoplasm, increased SERCA2 levels cause elevated neurotransmitter release, thereby enhancing LTP.
This mouse model, termed Df(16)1/+, contains hemizygous deletions in 23 genes on chromosome 16, homologous to the 22q11 DS region in humans. To determine the specific gene(s) involved in the elevated SERCA2 and enhanced plasticity phenotype, first author Laurie Earls and colleagues generated various mouse models with deletions in smaller regions of the Df(16)1 region, finding that only DGCR4 heterozygous (DGCR4+/-) mice replicated the age-dependent increase in LTP. This dovetails with evidence from the Karayiorgou/Gogos group at Columbia University, which also fingers DGCR4 as the main gene of interest in the deleted segment in terms of the neurobiological effects on the mice (see SRF related news story). DGCR4+/- mice also showed an upregulation in the level of SERCA2 in hippocampal synaptosomal preparations that was not observed in younger mice. In fact, inhibition of SERCA2 normalized LTP levels in DGCR4+/- slices.
Because DGCR4 is a gene involved in microRNA biogenesis, a process that negatively regulates protein translation, Earls and colleagues hypothesized that a loss of regulatory microRNAs underlies the elevated levels of SERCA2. Consistent with this idea, they observed a downregulation of several microRNAs in Df(16)1+ mice, including miR-25, -98, and -125. Expression of either miR-25 or miR-185 was able to reverse the increased LTP observed in the hippocampus of DGCR4+/- mice and significantly decrease SERCA2 protein levels.
Consistent with a role for SERCA2 in schizophrenia, protein levels of the ATPase were significantly increased in both the hippocampus and prefrontal cortex of subjects with schizophrenia. Although the authors did not measure microRNA levels in this tissue, their finding that the binding sites of miR-25 and miR-185 on SERCA2 are conserved between mouse and humans suggests that these microRNAs are “a potential mechanism for the observed SERCA2 protein overexpression in schizophrenia.”—Allison A. Curley.
Earls LR, Fricke RG, Yu J, Berry RB, Baldwin LT, Zakharenko SS. Age-Dependent MicroRNA Control of Synaptic Plasticity in 22q11 Deletion Syndrome and Schizophrenia. J Neurosci . 2012 Oct 10 ; 32(41):14132-44. Abstract
Meechan DW, Tucker ES, Maynard TM, Lamantia AS. CXCR4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome. Proc Natl Acad Sci U S A . 2012 Oct 22. Abstract