Article

mGluR5 in Cortical Excitatory Neurons Exerts Both Cell-Autonomous and -Nonautonomous Influences on Cortical Somatosensory Circuit Formation

The Cain Foundation Laboratories, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 12/2010; 30(50):16896-909. DOI: 10.1523/JNEUROSCI.2462-10.2010
Source: PubMed

ABSTRACT Glutamatergic neurotransmission plays important roles in sensory map formation. The absence of the group I metabotropic glutamate receptor 5 (mGluR5) leads to abnormal sensory map formation throughout the mouse somatosensory pathway. To examine the role of cortical mGluR5 expression on barrel map formation, we generated cortex-specific mGluR5 knock-out (KO) mice. Eliminating mGluR5 function solely in cortical excitatory neurons affects, not only the whisker-related organization of cortical neurons (barrels), but also the patterning of their presynaptic partners, the thalamocortical axons (TCAs). In contrast, subcortical whisker maps develop normally in cortical-mGluR5 KO mice. In the S1 cortex of cortical-mGluR5 KO, layer IV neurons are homogenously distributed and have no clear relationship to the location of TCA clusters. The altered dendritic morphology of cortical layer IV spiny stellate neurons in cortical-mGluR5 KO mice argues for a cell-autonomous role of mGluR5 in dendritic patterning. Furthermore, morphometric analysis of single TCAs in both cortical- and global-mGluR5 KO mice demonstrated that in these mice, the complexity of axonal arbors is reduced, while the area covered by TCA arbors is enlarged. Using voltage-clamp whole-cell recordings in acute thalamocortical brain slices, we found that KO of mGluR5 from cortical excitatory neurons reduced inhibitory but not excitatory inputs onto layer IV neurons. This suggests that mGluR5 signaling in cortical excitatory neurons nonautonomously modulates the functional development of GABAergic circuits. Together, our data provide strong evidence that mGluR5 signaling in cortical principal neurons exerts both cell-autonomous and -nonautonomous influences to modulate the formation of cortical sensory circuits.

Download full-text

Full-text

Available from: Li-Jen Lee, Aug 05, 2014
1 Follower
 · 
144 Views
  • Source
    • "It is well known that disrupting the expression of genes regulating the neuronal activity of cortical neurons cause defects in the formation of the barrel walls around TCAs clusters (Fig. 4). For instance, cortical invalidation of mGluR5 (the group I metabotropic receptor 5) leads to a defect in wall organization in S1 with no effect on TCAs clustering [119] [120] [121]. Similarly, invalidation of PKARIIb [122] [123] or of cortical NR1 (N-methyld-aspartate receptor, subunit1) [124] allows TCAs clustering but specifically disrupts the reorganization of cortical neurons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sensory perception relies on the formation of stereotyped maps inside the brain. This feature is particularly well illustrated in the mammalian neocortex, which is subdivided in distinct cortical sensory areas that comprise topological maps, such as the somatosensory homunculus in human or the barrel field of the large whiskers in rodents. How somatosensory maps are formed and relayed into the neocortex remain essential questions in developmental neuroscience. Here, we will present our current knowledge on whisker map transfer in the mouse model, with the goal of linking embryonic and postnatal studies into a comprehensive framework.
    Seminars in Cell and Developmental Biology 11/2014; 35. DOI:10.1016/j.semcdb.2014.07.005 · 5.97 Impact Factor
  • Source
    • "Together, these results suggest that mGluR5-mediated local synthesis of Arc may target a synapse for elimination. In support of this idea, brain-wide or cortexrestricted deletion of mGluR5 results in enhanced excitatory synaptic function and dendritic spines onto layer 4 neocortical neurons (Ballester-Rosado et al., 2010). We report here that postsynaptic deletion of mGluR5 in individual CA1 pyramidal neurons in vivo caused an increase in evoked EPSCs and implicate a cell-autonomous role for mGluR5 in suppression of synapse function or number during development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Experience refines synaptic connectivity through neural activity-dependent regulation of transcription factors. Although activity-dependent regulation of transcription factors has been well described, it is unknown whether synaptic activity and local, dendritic regulation of the induced transcripts are necessary for mammalian synaptic plasticity in response to transcription factor activation. Neuronal depolarization activates the myocyte enhancer factor 2 (MEF2) family of transcription factors that suppresses excitatory synapse number. We report that activation of metabotropic glutamate receptor 5 (mGluR5) on the dendrites, but not cell soma, of hippocampal CA1 neurons is required for MEF2-induced functional and structural synapse elimination. We present evidence that mGluR5 is necessary for synapse elimination to stimulate dendritic translation of the MEF2 target gene Arc/Arg3.1. Activity-regulated cytoskeletal-associated protein (Arc) is required for MEF2-induced synapse elimination, where it plays an acute, cell-autonomous, and postsynaptic role. This work reveals a role for dendritic activity in local translation of specific transcripts in synapse refinement.
    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.035 · 8.36 Impact Factor
  • Source
    • "Hence it is essential to understand the role mGluR5 plays in dendritic spine morphology and density, which are anatomical correlates of synaptic functioning. Although several studies have reported the crucial role of mGluR5 in the neurodevelopmental role of the cerebral cortex [24] [27] [2], the full spectrum of its impact on the dendritic spine quantities and morphological phenotypes remains elusive. Here, we report the effect of on layer 4 spiny neurons of deliberately knocking out the mGluR5 component in mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alterations in dendritic spine densities and morphologies have been correlated with the abnormal functioning of the synapse. Specifically the metabotropic glutamate receptor 5 (mGluR5) has been implicated in dendrogenesis and spineogenesis, since its activation triggers various signaling cascades that have been demonstrated to play roles in synaptic maturation and plasticity. Here we used the Golgi impregnation technique to analyze the dendritic spines of mGluR5(-/-) knockout mice in comparison to their heterozygote mGluR5(+/-) littermates. mGluR5(-/-) mice had elevated spine densities irrespective of spine type or location along their dendritic trees in comparison to mGluR5(+/-) animals. Such anatomical changes may underlie the hyperexcitability observed in mGluR5 total knockout mice.
    Neuroscience Letters 07/2012; 524(1):65-8. DOI:10.1016/j.neulet.2012.07.014 · 2.06 Impact Factor
Show more