Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

Abstract

Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR-GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR-GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn-mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1-mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1-mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.

Keywords: ADHD; Elfn1; Elfn2; PTSD; dopaminergic system; habenular circuit; inhibitory interneurons; mGluR7.

Figure 1

Trans-synaptic interactions between leucine-rich-repeat (LRR) and fibronectin type III domain-containing transmembrane proteins (LRRFn) and metabotropic glutamate receptor (mGluR) proteins in the hippocampal CA1 circuits and function of extracellular leucine-rich repeat fibronectin domain-containing family proteins (Elfn1) in the retinal synapses. (A) Domain structure of Elfn1 and Elfn2. (B) Molecular phylogenetic tree of G protein-coupled receptor (GPCR; simplified tree from Fredriksson et al., 2003) and physical interaction between GPCR and LRRFn. (C) Distribution of Elfn1 protein in the hippocampus (reprinted from Tomioka et al., 2014). DG, dentate gyrus; HIPP, hilar perforant path-associated; OLM, oriens-lacunosum-molecule cells; SO, stratum oriens; SP, stratum pyramidale, SR, stratum radiatum; SLM, stratum lacunosum moleculare; SUB, hippocampal subiculum. (D) Two major inputs in CA1 and feedback inhibition by Elfn1-expressing interneurons (INs). Ipsi- and contra-lateral CA3 region inputs into dendritic domains of CA1 pyramidal neurons in the SR via Schaffer collaterals. The entorhinal cortexinputs into the SLM. Elfn1 is expressed in OLM cells and HIPP cells, which are GABAergic interneurons located in the SO of CA1 and the hilus of the dentate gyrus, respectively. Hippocampal CA1 circuits regulated by LRRFn–mGluR trans-synaptic interactions. (E) Trans-synaptic interactions of mGluR7 and Elfn1 formed between pyramidal cells and OLM cells. (F) Trans-synaptic interactions of Elfn2 with group III mGluR candidates such as mGluR4, mGluR7, and mGluR8 between excitatory neurons. (G) Trans-synaptic interactions among FLRT3, teneurin 2, and Lphn3 between CA3 and CA1 excitatory connections in the SR. Lphn2 is exclusively localized in the SLM and involved in the excitatory synapse formation between the entorhinal cortex and CA1 (Sando et al., 2019). (H) Decrease in the association of mGluR7- and mGluR1-positive signals in the CA1 of Elfn1-knockout (KO) mice (reprinted from Tomioka et al., 2014). (I) Retinal synapses among cone and rod photoreceptor cells and bipolar cells. ONL, outer nuclear layer; OPL, outer plexiform; INL, inner nuclear layer; IPL, inner plexiform layer. ON and OFF indicate the stratified IPL where circuits respond to the onset and offset of light, respectively. Elfn1 and Elfn2 are selectively expressed in the matured rod and cone cells, respectively, that synapse onto ON-bipolar cells in the OPL. (J) Elfn1 bridges the functional interaction between the glutamate release-directing Ca_V1.4 channel and glutamate-sensing mGluR6 (Cao et al., 2015). (K) Cone cells express Elfn1 during early synaptogenesis and switch to ELFN2 to support synaptic signaling in mature retinas (Cao et al., 2020).

Figure 2

Roles of Elfns–mGluRs trans-interaction in synapses. (A) Roles of Elfn1 in hippocampal and cortical synapses on somatostatin-interneurons (SST-INs). (B) Role of Elfn2 in hippocampal synapses. (C) Dopaminergic and habenular neural circuits for ADHD (Lee and Goto, 2013).