Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease

Abstract

Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions, including the neocortex, hippocampus, midbrain, striatum, and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning, and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimer's disease, Parkinson's disease, and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease.

Figure 1. mGluR-LTD in health and disease

Experimental evidence suggest the involvement of mGluR-LTD in goal directed learning, and cerebellar circuit adjustment during motor learning. Excessive mGluR-LTD has been linked to Alzheimer disease and Fragile X syndrome, while a loss of mGluR-LTD in the striatum may contribute to Parkinson’s symptoms. Finally, reduced mGluR-LTD in the midbrain has been suggested to confer a vulnerability of drug addiction. The group 1 mGluRs, mGluR1 and mGluR5 are differentially expressed in most brain regions, and co-expressed in some, based on (Ferraguti and Shigemoto, 2006). mGluR1 expression is indicated by the diagonal lines and mGluR5 expression pattern is indicated by the dotted stipple. Gray stipple indicates a lower level of expression.

Figure 2. Striatal mGluR-LTD controls indirect pathway activity

In medium spiny neurons of the dorsal striatum, excitatory afferents from the cortex and dopamine fiber arising from the substantia nigra converge. If Gp1 mGluRs and D2Rs are activated concomitantly endocannabinoids. most likely anandamide, are synthesized and released from the MSN. This retrograde messenger activates presynaptic CB1 receptors, and reduced release probability via inhibition of calcium channels, cAMP and PKA, such that Rab3a and Rim1a dependent exocytosis is reduced. In Parkinson’s disease dopamine afferents are absent, and mGluR-LTD as a consequence reduced. This leads to increased indirect pathway activity (i.e. more inhibitory output from the GABAergic MSNs) and a reduction of spontaneous movements.

Figure 3. mGluR reverses cocaine-evoked synaptic plasticity

Excitatory afferents onto dopamine neurons of the VTA are potentiated after cocaine exposure by the insertion of GluR2-lacking AMPARs. This drug-evoked plasticity can be reversed by mGluR-LTD elicited by strong activation of the excitatory afferents.

Figure 4. Mechanisms of translation-dependent mGluR-LTD: Implications for Fragile X Syndrome

A. In normal (or wildtype) hippocampal CA1 neurons brief activation of mGluR1/5 triggers rapid endocytosis of AMPARs through TACE mediated intramembrane cleavage of NPR. mGluR-stimulated AMPAR endocytosis requires activity of the Tyr phosphatase STEP as well as existing Arc protein. MGluRs also trigger translation of proteins through activation of translation initiation, as well as dephosphorylation of the RNA binding protein, FMRP. Known proteins whose synthesis is stimulated by mGluRs as well as play a role in mGluR-LTD include Step, Map1b, Arc and APP. These proteins are known to regulate and/or stimulate AMPAR endocytosis. B. In the absence of FMRP, as in Fragile X Syndrome, mGluRs stimulate endocytosis of AMPARs, but it is unknown if the mechanisms are similar to those at normal synapses. In Fmr1 KO mice, there are increased steady state translation rates and protein levels of MAP1b and APP, as well as a deficit in mGluR stimulation of translation. mGluR-LTD in the Fragile X Syndrome mouse model (Fmr1 KO mice) is enhanced and independent of translation suggesting that the “LTD proteins” are available to maintain persistent decreases in AMPARs and LTD.