The Complex Formed by Group I Metabotropic Glutamate Receptor (mGluR) and Homer1a Plays a Central Role in Metaplasticity and Homeostatic Synaptic Scaling

Abstract

G-protein-coupled receptors can be constitutively activated following physical interaction with intracellular proteins. The first example described was the constitutive activation of Group I metabotropic glutamate receptors (mGluR: mGluR1,5) following their interaction with Homer1a, an activity-inducible early-termination variant of the scaffolding protein Homer that lacks dimerization capacity (Ango et al., 2001). Homer1a disrupts the links, maintained by the long form of Homer (cross-linking Homers), between mGluR1,5 and the Shank-GKAP-PSD-95-ionotropic glutamate receptor network. Two characteristics of the constitutive activation of the Group I mGluR-Homer1a complex are particularly interesting: (1) it affects a large number of synapses in which Homer1a is upregulated following enhanced, long-lasting neuronal activity; and (2) it mainly depends on Homer1a protein turnover. The constitutively active Group I mGluR-Homer1a complex is involved in the two main forms of non-Hebbian neuronal plasticity: "metaplasticity" and "homeostatic synaptic scaling," which are implicated in a large series of physiological and pathologic processes. Those include non-Hebbian plasticity observed in visual system, synapses modulated by addictive drugs (rewarded synapses), chronically overactivated synaptic networks, normal sleep, and sleep deprivation.

Figure 1.

Spine signaling under basal conditions and after activation induced Homer1a accumulation. A, Under basal conditions, glutamate receptors, channels, and intracellular platform proteins are cross-linked by cross-linking Homers. B, After neuronal activity induced Homer1a accumulation, spine signaling is remodeled. B1, The constitutively active mGluR1,5-Homer1a complex triggers dephosphorylation and internalization of AMPARs (left), physically interacts and inhibits NMDARs (middle), and allows the constitutive activation of PI3-kinase and mTOR (right). B2, Homer1a also frees cross-linked Ca²⁺ channels, increasing their activity (TRPC and L-VDCC, left) while the constitutively active mGluR1,5-Homer1a complex increases PLC activation, leading to increased activity of IP3 receptors and thus Ca²⁺ release from the ER (mGluR1/5 agonist-independent increase in IP3R Ca²⁺ release, right). *The mGluR1,5 receptors or TRPC channel are constitutively activated.

Figure 2.

The constitutively active mGluR1,5-Homer1a complex strongly activates BigK channels in cerebellar granule cells. Left, Under basal conditions, mGluR1 and Shank are cross-linked by Homer 3. Transient activation of mGluR1 by an mGluR1,5 agonist (DHPG) activates, in a reversible manner, BigK channels recorded in cell-attached patches (physiological recordings shown underneath). Right, Homer3 antisense or activity-induced Homer1a induction releases mGluR1 from cross-linking, and they become constitutively active. This leads to constitutive activation of BigK channels recorded in cell-attached patches (physiological recordings shown underneath). The BigK channels are recorded in cell-attached patches. Application of DHPG does not further activate these channels, whereas application of an mGluR1 inverse agonist (Bay 36-7620), but not a neutral antagonist (not shown), inhibits the constitutive activation of BigK channels. *The mGluR1,5 receptors are constitutively activated.

Figure 3.

Sliding threshold metaplasticity in the visual system and in cortico-striatal excitatory rewarded and unrewarded synapses. A, Synapses between lateral intracortical neurons and V1 layer 2/3 (L2/3) pyramidal neurons. When a DE is reversed by an LE, sliding homeostatic plasticity occurs. Newly synthetized Homer1a constitutively activates mGluR5, which inhibits NMDARs through a direct interaction (Chokshi et al., 2019b). This leads to an increase in the threshold required for LTP induction. B, Cortico-striatal synapses. Two types of sliding homeostatic plasticity occur. In the absence of D1 dopamine receptor stimulation, activation of these synapses (unrewarded synapses) triggers, in downstream striatal neurons, similar signaling events as we have seen above in the visual system after LE. A decrease in the LTP/LTD ratio is observed. In contrast, when D1 receptors are activated before activation of the cortico-striatal synapses (rewarded synapses), Homer1a is synthetized constitutively and activates mGluR5. In addition, the D1 receptor-cAMP-ERK activated pathway allows the phosphorylation and isomerization (by PIN) of mGluR5. The phosphorylated and isomerized mGluRs activate (instead of inhibiting) NMDARs by an unknown mechanism, leading to an increase in the LTP/LTD ratio (Marton et al., 2015). *The mGluR1,5 receptors are constitutively activated.

Figure 4.

Homeostatic glutamatergic synaptic downscaling during sleep periods. During wake periods, cross-linking Homers are fully operational. Neuronal activity-induced Homer1a accumulates outside the dendritic spine because spine entry is blocked by α- and β-activated adrenergic receptors via an unknown mechanism. During a sleep period, Homer1a entry into spine is facilitated by the activation of adenosine A1 receptors via an unknown mechanism. The constitutively active mGluR1,5-Homer1a complex increases the dephosphorylation of AMPARs. This induces homeostatic downscaling glutamatergic synapses. *The mGluR1,5 receptors are constitutively activated.

Figure 5.

Homeostatic mPFC glutamatergic synaptic upscaling during SD: an antidepressant treatment. The molecular mechanisms by which SD modifies mPFC excitatory synapses have been recently deciphered, at least in part (Holz et al., 2019). A Tat-Homer1a cell-permeable peptide, disconnecting mGluR5 from cross-linking Homer, mimics the signaling pathways and antidepressant effect of SD. This peptide and SD activate mTOR signaling and AMPAR translation, a key step in antidepressant therapeutic effect. These signaling events are triggered by the constitutive mGluR5-Homer1a complex because they are blocked by MPEP, an inverse agonist of mGluR5. mTOR is also activated by TrkB. *The mGluR1,5 receptors are constitutively activated.