Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures

Abstract

GABAergic interneurons are highly heterogeneous, and much is unknown about the specification and functional roles of their neural circuits. Here we show that a transinteraction of Elfn1 and mGluR7 controls targeted interneuron synapse development and that loss of Elfn1 results in hyperactivity and sensory-triggered epileptic seizures in mice. Elfn1 protein increases during postnatal development and localizes to postsynaptic sites of somatostatin-containing interneurons (SOM-INs) in the hippocampal CA1 stratum oriens and dentate gyrus (DG) hilus. Elfn1 knockout (KO) mice have deficits in mGluR7 recruitment to synaptic sites on SOM-INs, and presynaptic plasticity is impaired at these synapses. In patients with epilepsy and attention deficit hyperactivity disorder (ADHD), we find damaging missense mutations of ELFN1 that are clustered in the carboxy-terminal region required for mGluR7 recruitment. These results reveal a novel mechanism for interneuron subtype-specific neural circuit establishment and define a common basis bridging neurological disorders.

Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision

“…Interestingly, mGluR7 identified in a previous study as a binding partner for ELFN1 (Tomioka et al, 2014) is homologous to mGluR6 and belongs to the same subfamily. In both retina and hippocampus interactions involving ELFN1 occur trans -synaptically and are involved in positioning glutamate GPCRs at discrete subcellular locations.…”

“…At those synapses ELFN1 was shown to act across the synapse to inhibit synaptic vesicle release probability at presynaptic terminals of CA1 neurons. A subsequent study further determined that the effect on release probability is likely mediated by presynaptic mGluR7, with which ELFN1 was found to form trans -synaptic contacts (Tomioka et al, 2014). However, the mechanistic role of ELFN1 in the hippocampus appears to differ from the retina.…”

“…However, the mechanistic role of ELFN1 in the hippocampus appears to differ from the retina. In hippocampal neurons it is expressed postsynaptically and acts to regulate presynaptic release mechanisms (Sylwestrak and Ghosh, 2012; Tomioka et al, 2014). Furthermore, ELFN1 at these synapses has no impact on the physical connectivity of hippocampal neurons, and its loss does not abolish synaptic transmission.…”

“…This broader expression is reflected by marked behavioral alterations associated with the loss of ELFN1 that include hyperactivity, seizures, and an abnormal response to psychostimulants (Dolan and Mitchell, 2013). Accordingly, mutations in ELFN1 were also found to be associated with epilepsy in humans (Tomioka et al, 2014). These observations suggest that ELFN1 may affect several circuits in the brain outside of hippocampus.…”

Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications

“…ELFN1 has been implicated to be associated with seizures and ADHD in both human clinical samples and animal models (Tomioka et al, 2014; Dolan and Mitchell, 2013). The expression of ELFN1 localizes mostly to excitatory postsynaptic sites (Sylwestrak and Ghosh, 2012) and recent studies show that the ELFN1 gene specifically controls short-term plasticity, which denotes changes in synaptic strength that last up to tens of seconds, at some synapse types (Blackman et al, 2013).…”