Abstract
Type 1 metabotropic glutamate receptors (mGluR1s) are key elements in neuronal signaling. While their function is well documented in slices, requirements for their activation in vivo are poorly understood. We examine this question in adult mice in vivo using 2-photon imaging of cerebellar molecular layer interneurons (MLIs) expressing GCaMP. In anesthetized mice, parallel fiber activation evokes beam-like Cai rises in postsynaptic MLIs which depend on co-activation of mGluR1s and ionotropic glutamate receptors (iGluRs). In awake mice, blocking mGluR1 decreases Cai rises associated with locomotion. In vitro studies and freeze-fracture electron microscopy show that the iGluR-mGluR1 interaction is synergistic and favored by close association of the two classes of receptors. Altogether our results suggest that mGluR1s, acting in synergy with iGluRs, potently contribute to processing cerebellar neuronal signaling under physiological conditions.
Highlights
A considerable body of data, spanning from genomics and structural studies of receptors to functional studies at the synaptic level, indicates that glutamate released at excitatory synapses of the mammalian nervous system binds to both ionotropic and type 1 metabotropic receptors and engages a complex pattern of signaling pathways often involving a synergistic action of both receptors
Glutamate released by parallel fibers (PFs) binds to receptors on Purkinje cells (PCs) and on molecular layer interneurons (MLIs), which form an interconnected circuit governing the output of the cerebellar cortex
The absence of GCaMP expression in PCs is further illustrated in Figure 1B, which shows no overlap between GCaMP3 and calbindin (CB), a protein that is absent from MLIs but has a strong expression in PCs
Summary
A considerable body of data, spanning from genomics and structural studies of receptors to functional studies at the synaptic level, indicates that glutamate released at excitatory synapses of the mammalian nervous system binds to both ionotropic (iGluRs) and type 1 metabotropic receptors (mGluR1s) and engages a complex pattern of signaling pathways often involving a synergistic action of both receptors (reviewed in Reiner and Levitz, 2018). Patterns of PF activity convey information on the sensorimotor state of the animal (review by Jorntell, 2017) and determine the recruitment of MLIs through PF-MLI synapses (Bao et al, 2010). From work in brain slices it is known that several types of iGluRs (Carter and Regehr, 2000) as well as mGluR1s (Karakossian and Otis, 2004; Collin et al, 2009) are activated in MLIs by synaptically released glutamate.
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