Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development

Abstract

Loerwald KW, Patel AB, Huber KM, Gibson JR. Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development. J Neurophysiol 113: 786 -795, 2015. First published November 12, 2014 doi:10.1152/jn.00465.2014.-Both short-and long-term roles for the group I metabotropic glutamate receptor number 5 (mGluR5) have been examined for the regulation of cortical glutamatergic synapses. However, how mGluR5 sculpts neocortical networks during development still remains unclear. Using a single cell deletion strategy, we examined how mGluR5 regulates glutamatergic synaptic pathways in neocortical layer 2/3 (L2/3) during development. Electrophysiological measurements were made in acutely prepared slices to obtain a functional understanding of the effects stemming from loss of mGluR5 in vivo. Loss of postsynaptic mGluR5 results in an increase in the frequency of action potential-independent synaptic events but, paradoxically, results in a decrease in evoked transmission in two separate synaptic pathways providing input to the same pyramidal neurons. Synaptic transmission through ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not N-methyl-D-aspartate (NMDA) receptors, is specifically decreased. In the local L2/3 pathway, the decrease in evoked transmission appears to be largely due to a decrease in cell-to-cell connectivity and not in the strength of individual cell-to-cell connections. This decrease in evoked transmission correlates with a decrease in the total dendritic length in a region of the dendritic arbor that likely receives substantial input from these two pathways, thereby suggesting a morphological correlate to functional alterations. These changes are accompanied by an increase in intrinsic membrane excitability. Our data indicate that total mGluR5 function, incorporating both short-and long-term processes, promotes the strengthening of AMPA receptor-mediated transmission in multiple neocortical pathways. metabotropic glutamate receptor; synapse; cortex GROUP I METABOTROPIC RECEPTORS (Gp1 mGluRs) consist of the two subtypes, mGluR1 and mGluR5. Over the first 4 wk of postnatal development, their expression and function are strong (Dudek and Bear 1989;Jia et al. 1995). The mGluR5 subtype is expressed in all layers of the rodent somatosensory cortex and peaks in expression during the first 3 wk of life (Munoz et al. 1999;Wijetunge et al. 2008).

Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system

“…One of the most striking features of mGlu5 receptors is that agonist-stimulated PI hydrolysis is extraordinarily large during the first 10 days of postnatal life, and progressively declines afterwards (Nicoletti et al, 1986a; Casabona et al, 1997). mGlu5 receptors are involved in mechanisms of developmental plasticity, and drive key events in the formation of the cortical somatosensory map (Hannan et al, 2001; Wijetunge et al, 2008; Loerwald et al, 2015; Ballester-Rosado et al, 2016). mGlu5 receptors are necessary for the development of fast-spiking GABAergic interneurons, which regulate the synchronous firing of pyramidal neurons and are critical for the generation of network oscillations in the PFC (Barnes et al, 2015; Luoni et al, 2016).…”

Novel phospho-switch function of delta-catenin in dendrite development

“…Cultured primary hippocampal neurons treated with glutamate develop significantly more complex dendritic arbors when compared with controls, whereas blocking activity of glutamate receptors results in the formation of less complex dendritic arbors ( Charych et al, 2006 ; Hamad et al, 2011 ; Previtera and Firestein, 2015 ). Both hippocampal and cortical neurons of mice lacking Grm5 , the gene that encodes the glutamate receptor mGluR5, develop significantly less complex dendritic arbors than controls in vivo ( Ballester-Rosado et al, 2010 ; Loerwald et al, 2015 ). Further, cultured neurons treated with the type 1 mGluR (mGluR1 and mGluR5) agonist 3,5-dihydroxyphenylglycine (DHPG) exhibit increased dendrite growth during early development ( Cruz-Martín et al, 2012 ).…”

Lrrc7 mutant mice model developmental emotional dysregulation that can be alleviated by mGluR5 allosteric modulation

“…It has been well-established that mGluR5 regulates synaptic strength 34–36 , and indirect evidence shows that mGluR5 also plays a role in early neurite development. In the zebrafish model of Fragile X syndrome, pharmacological mGluR5 inhibition corrects neurite branching defects 37 ; whereas in mice, deletion of mGluR5 in layer 2/3 pyramidal neurons of somatosensory cortex impairs dendritic arborization 38 . The link between mGluR5 and scaffold proteins in neurite morphogenesis and the underlying signaling remains unexplored.…”