Dr. Peter Scheiffele is a professor at the Biozentrum, University of Basel, where his group studies the molecular mechanisms underlying formation of neuronal circuits both in health and diseases such as autism. Dr. Scheiffele’s pioneering work on how trans-synaptic signals such as neuroligin and neurexin promote synapse formation and stabilization has led the field for over two decades. Currently, the group is interested in alternative splicing as a generator of the molecular diversity underlying synaptic specificity, as well as the role of autism risk factors such as neuroligin-3 (Nlgn3) in social behaviors. In the former domain, among other discoveries, the Scheiffele group found RNA-binding protein SLM2 as a highly specific controller of glutamatergic synapse plasticity: correction of one exon target of SLM2 could restore plasticity and behavioral defects in Slm2 knockout (KO) mice. In the latter domain, the Scheiffele group’s continuing work on mice deficient in Nlgn3 in ventral tegmental area (VTA) dopaminergic (DA) neurons has connected genetic autism risk factor Nlgn3 to oxytocinergic signaling, with the common thread of translation regulation and plasticity.
In work published in Nature in August 2020, Hörnberg et al. from the Scheiffele group both identify Nlgn3 in VTA DA neurons as a key mediator of autism-related social behaviors and find a small molecule that can reverse these deficits of Nlgn3 KO mice. The key findings of this work rest on a behavioral assay of social recognition in juvenile mice (postnatal day (P) 26-28) and electrophysiology on acute midbrain slices in the same juvenile mice. For the behavioral assay, the authors wanted to recapitulate interactions characteristic of some patients with autism, which include lower scoring on face identity recognition tasks. In the task Hörnberg et al. used, experimental mice were repeated exposed to the same same-sex mouse four times, after which they were exposed to a novel same-sex mouse (Fig 1a). During the last interaction, the experimental mice were scored for time spent interacting with the novel mouse (Fig 1b). For the electrophysiology, the authors were interested in the firing rate of VTA DA neurons at baseline, with oxytocin in the bath, and with experimentally treated mice; for this they recorded spontaneous currents under a voltage-clamped cell-attached setup.
In their initial characterizations, the authors found that for Nlgn3 KO mice, VTA DA oxytocin response is altered at both cellular and behavioral levels. In wild-type (WT) mice, hypothalamic neurons release the peptide oxytocin in the VTA, and this increases the firing of VTA DA neurons projecting to the nucleus accumbens (NAc). This circuit is thought to underlie social behaviors such as social novelty response and reinforcement. Hörnberg et al. found that constitutive Nlgn3 KO mice had a decreased social novelty response (Fig 1b), that this effect was specific to VTA DA neurons (Fig 1h) (behaviors could be recapitulated with selective miRNA KD of Nlgn3 in VTA DA neurons), and that this effect could be reverse with selective re-expression of Nlgn3 in the VTA DA neurons of Nlgn3 KO mice (Fig 1e). Thus, Nlgn3 in VTA DA neurons is both necessary and sufficient for social novelty response. Furthermore, acute slice electrophysiology showed that Nlgn3 KO VTA DA neurons had lower baseline firing rate (Fig 1p) as well as no increase in firing rate induced by oxytocin in the bath (Fig 1q).
The authors then sought to understand the mechanism underlying Nlgn3’s effect on oxytocin response, in the hopes of finding a target for therapeutic restoration of social novelty response. Interestingly, both metabolic labeling studies as well as shotgun proteomics on VTA DA neurons showed dysregulation (specifically, an increase) in mRNA translation. This effect on translation is similar to that observed in other models of autism such as Fragile X Syndrome. Drawing from this literature, the authors selected MAP kinase-interacting kinases (MNKs), mediators of signaling-dependent changes in mRNA translation, as potential targets. The authors found that the highly specific MNK inhibitor ETC-168 not only crosses the blood-brain barrier, but also, when dosed orally in mice, increases the baseline firing of VTA DA neurons (Fig 2b), increases VTA DA neurons’ responsiveness to bath oxytocin (Fig 2c), and increases social novety response (Fig 2e). Given that the electrophysiology results were obtained in slices two hours after the last ETC-168 dose, the known linking of mRNA translation to neuronal plasticity, and recent research on the importance of plasticity in VTA DA neurons, the authors hypothesize that MNK inhibition restores Nlgn3 KO oxytocin responses via a plasticity effect.
The above work finds a link between a genetic autism risk factor, oxytocin signaling, and social behaviors, and it further connects these factors with the finding that a therapeutic small molecule can reverse cellular and behavioral oxytocin response deficits in a genetic model of autism. More generally, the findings also suggest that common features of autism—such as dysregulated translation and synaptic properties—might be targeted as a way to overcome the genetic heterogeneity within autism spectrum disorders. This most recent advance highlights the breadth and trajectory of Dr. Scheiffele’s work: with understandings derived from basic research into the mechanisms underlying the development of neurons, we can accelerate development of therapeutics of diseases previously thought to be intractable.
To learn more about Dr. Scheiffele’s research and recent work, please join us for the talk, “Building functional circuits: From RNA splicing to Autism”, on Tuesday, April 20th at 9am on Zoom.
https://uchealth.zoom.us/j/81547662915
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References
Hörnberg, H., Pérez-Garci, E., Schreiner, D., Hatstatt-Burklé, L., Magara, F., Baudouin, S., Matter, A., Nacro, K., Pecho-Vrieseling, E., and Scheiffele, P. (2020). Rescue of oxytocin response and social behaviour in a mouse model of autism. Nature 584, 252–256.
Scheiffele, P., Fan, J., Choih, J., Fetter, R., and Serafini, T. (2000). Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons. Cell 101, 657–669.
Traunmuller, L., Gomez, A.M., Nguyen, T.-M., and Scheiffele, P. (2016). Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 352, 982–986.
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Dr. Scheiffele’s Website
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James Deng is a first year PhD student in the Neurosciences Graduate Program at UCSD. He is a member of Nicola Allen’s group at the Salk Institute for Biological Studies, where he studies the role of astrocyte signaling and astrocyte-secreted proteins in neurodevelopmental disorders.
UCSD Neurosciences 