ELFN1 trafficking and synaptic enrichment
Fig 1. Diagram of a synapse between a rod photoreceptor and rod bipolar cell.
Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that are activated by glutamate. A subset of mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) can interact trans-synaptically with ELFN proteins, and these interactions promote mGluR synaptic localization (1–5). At rod photoreceptor synapses in the retina, presynaptic ELFN1 interacts with postsynaptic mGluR6 (Fig 1). Elfn1 knockout mice have structural and functional deficits at this synapse, including loss of mGluR6 (2).
We demonstrated that in mGluR6 null mice, ELFN1 is still trafficked to rod spherules, but it is dramatically less abundant (Fig 2), and within the spherules, colocalization with synapse markers is reduced (Fig 3) (6). Furthermore, we found that expressing mGluR6-EGFP in bipolar cells of mGluR6 null mice rescued ELFN1 synaptic enrichment (Fig 4) (6).
Fig 4. Expression of mGluR6-EGFP in mGluR6 null bipolar cells rescues ELFN1 localization. Adapted from (6).
Our results demonstrate that at rod synapses, mGluR6 mediates retrograde trans-synaptic stabilization of ELFN1. Ongoing projects aim to characterize ELFN1 trafficking and determinants of synaptic localization.
References
1. Tomioka NH, Yasuda H, Miyamoto H, et al. 2014. Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures. Nat Commun 5, 1–16.
2. Cao Y, Sarria I, Fehlhaber KE, et al. 2015. Mechanism for selective synaptic wiring of rod photoreceptors into the retinal circuitry and its role in vision. Neuron 87, 1248–1260.
3. Dunn HA, Patil DN, Cao Y, et al. 2018. Synaptic adhesion protein ELFN1 is a selective allosteric modulator of group III metabotropic glutamate receptors in trans. Proc Natl Acad Sci USA 115, 5022–5027.
4. Stachniak TJ, Sylwestrak EL, Scheiffele P, et al. 2019. Elfn1-induced constitutive activation of mGluR7 determines frequency-dependent recruitment of somatostatin interneurons. J Neurosci 39, 4461–4474.
5. Dunn HA, Zucca S, Dao M, et al. 2019. ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior. Mol Psychiatry 24, 1902–1919.
6. Lee J, McGowan R V, Agosto MA. 2025. Trans-synaptic interaction with mGluR6 contributes to ELFN1 presynaptic enrichment in rod photoreceptors. J Neurosci 45, e0785252025.