Developmental expression of mGlu2 and mGlu3 in the mouse brain
Graphical abstract
mGlu2 and mGlu3 show overlapping but distinct mRNA expression patterns across a developmental trajectory. Most notably the dentate gyrus strongly expresses mGlu2 but not mGlu3 from PN8 onwards, while the thalamic reticular nucleus exhibits high levels of mGlu3 mRNA in the absence of mGlu2 at all developmental time points assessed.
Introduction
Glutamate is the primary excitatory neurotransmitter in the brain, acting at ionotropic ligand-gated channels (Glu) and metabotropic G protein-coupled receptors (mGlu) to finely tune neuronal activity (Neki et al., 1996b,; Ohishi et al., 1998) reviewed in (Ferraguti and Shigemoto, 2006). Glutamate receptors have broad and overlapping expression patterns within the brain, and the metabotropic class comprises 8 distinct receptors that are further classified into 3 subgroups based upon their structure and function (Conn and Pin, 1997). Class I couple to Gq and activate signaling via phospholipase C. Class II couple to Gi/o, negatively regulating adenyl cyclase, as do Class III receptors (for review see Ferraguti and Shigemoto, 2006). Clinical and preclinical studies of class II mGlu receptors have examined their potential role in ranging from psychiatric (schizophrenia, drug abuse, depression) to neurological (epilepsy, stroke) (reviewed in Imre, 2007).
Class II mGlu receptors (e.g., mGlu2 and mGlu3) are found on different types of neurons where they act either presynaptically to inhibit adenyl cyclase, negatively regulating glutamate release into the synapse or postsynaptically where they negatively modulate excitability via intracellular mechanisms such as inhibition of adenylate cyclase, mTOR signaling, modulation of ion channels, and induction of long term depression (Anwyl, 1999). Receptors of the mGlu2/3 class can heterodimerize with each other and with other receptors (Gonzalez-Maeso et al., 2008, Doumazane et al., 2011), controlling release of GABA, monoamines and other neuropeptides (Cartmell et al., 2001, Coplan et al., 2001, Schoepp, 2001). In this way, mGlu2/3 play important roles at both sides of the synapse in modulating neuronal activity and brain function.
There is very little work attempting to distinguish between mGlu2 and mGlu3 pharmacology and function. This is largely due to the fact that mGlu2 and mGlu3 are highly conserved, and subtype-specific ligands have only recently been identified (Sheffler et al., 2010, Cid et al., 2012). Attempts to dissociate mGlu2 from mGlu3 suggest distinct roles and interactions for each subtype (Spooren et al., 2000, Linden et al., 2005, Hetzenauer et al., 2008). The temporal expression of mGlu2 and mGlu3 and the role of these receptors in brain development is also not well understood, and a systematic analysis of mGlu2 and mGlu3 expression across development has not previously been conducted in species used as model systems for CNS disorders. To address this lack of information, in this study we assess mGlu2 and mGlu3 mRNA expression in the mouse brain across development.
Section snippets
Animals
Mice were bred and housed under standard husbandry conditions, approved by the Institutional Animal Care and Use Committee, and monitored daily for birth dates. Mice were euthanized, whole brains dissected and fresh frozen in O.C.T.; PN1 mice were dissected in ice-cold PBS, while older brains were removed in ambient air (N = 3 per timepoint). All brains were stored at −80 °C prior to sectioning. 18 μm sections were cut directly onto SuperFrost Plus Slides on a Leica CM 3050 S cryostat, onto
mGlu2 expression across a developmental time-course
At postnatal day 1 (PN1), mGlu2 expression is observed in cortical layers IV and V (Fig. 1A). Strongest cortical expression is in somatosensory regions, with lower levels detected in the cingulate, insular, and parietal cortices, and the pyramidal layer of the piriform cortex. Diffuse punctate expression is observed in the dentate gyrus of the hippocampus (Fig. 1C). Subcortically, numerous thalamic nuclei express mGlu2 at this time point (detailed in Table 1). Strong expression is observed in
Discussion
In this study we mapped expression of mGlu2 and mGlu3 mRNA throughout development and in adulthood, in the mouse CNS. We show that while both mGlu2 and mGlu3 are each expressed across many brain regions, they display distinct regional localization. Expression of mGlu2 was most notable in cortical and hippocampal subregions with high enrichment in the dentate gyrus; cortical mGlu2 appeared to decline across the time periods assessed, while concentration in the dentate gyrus increased from PN1 to
Conflict of interest
The authors have no conflicts of interest to declare.
Author contribution statement
All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CEM, EYD, JAG. Acquisition of data: CEM, EYD. Analysis and interpretation of data: CEM, EYD. Drafting of the manuscript: CEM. Critical revision of the manuscript for important intellectual content: EYD, JAG. All authors have approved the final manuscript.
Acknowledgements
The authors would like to thank Joshko Ivica and Anil Jonathan for their assistance with animal husbandry, and Indigo Pratt Kelly for her contributions to the microscopy. Over the course of these experiments, the investigators were supported by several grants. CEM was supported by an NHMRC overseas biomedical research fellowship (628906), and a Brain and Behavior Research Foundation Young Investigator award (19543). JAG was supported by NIMH (2R01MH080116-06A1), EYD was supported by NIMH (
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