The goal of research in the Scheiffele Lab is to understand molecular mechanisms underlying the formation of neuronal circuits in health and disease. Synapses are the key processing units in neuronal circuits. Therefore, we are examining mechanisms of synapse formation and synaptic re-arrangements in the central nervous system. We are exploring the trans-synaptic signals that coordinate the choice of synaptic partners, assembly of synaptic junctions and stabilization of appropriate contacts.
Alternative splicing programs for neuronal synapse specification
Neuronal networks in the mammalian brain represent one of the most complex examples of a highly organized biological system. The finite number of protein-coding genes in the human genome severely limits the genetic resources that can be employed for generating molecular diversity. Highly polymorphic cell surface receptor families arising from extensive alternative splicing provide attractive candidates for neuronal recognition. One of the main projects in our laboratory explores whether neuronal cell type-specific alternative splicing programs control key aspects of synaptic specificity.
We systematically mapped ribosome-associated transcript isoforms in genetically-defined neuron types of the mouse forebrain. This dataset provides an extensive resource of transcript diversity across major neuron classes (Furlanis et al., Nature Neuroscience, 2019). Neuronal transcript isoform profiles reliably distinguish even closely-related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex. These highly specific transcript isoform programs selectively control synaptic proteins and intrinsic neuronal properties.
In functional studies we uncovered RNA-binding proteins that are selectively expressed in specific neuronal cell classes and regulate alternative splicing programs in these cells. Remarkably, some of these splicing regulators control only a very narrow set of synaptic proteins and direct specific plasticity properties (Traunmüller et al., Science, 2016). These studies uncovered cell type-specific transcript diversification by alternative splicing is a central mechanism for the functional specification of neuronal cell types and circuits.
A longer-term prospect of this work is the development of specific splicing therapeutics that may enable the modification of neuronal circuit properties through highly targeted, specific interventions.
Synaptic basis of social recognition and social interaction in mice
Several components of the synaptic recognition systems we have studied over the past years have emerged as genetic risk factors for autism-spectrum disorders. We used a combination of chemicogenetics and conditional mutations to test the hypothesis that defects in synapse specification arising from autism-associated mutations result in specific disruptions in social behavior of mice. We specifically focus on the reward system and neural circuits that control social recognition in mice.
We discovered loss of the autism risk factor neuroligin-3 in dopaminergic cells of the ventral tegmental area (VTA DA neurons) alters social novelty exploration and the reinforcing properties of social stimuli (Bariselli et al., Nature Communications, 2018). Interestingly, the mutant mice exhibit normal interactions with novel objects, indicating that the phenotypes are selective for social stimuli. Social novelty exploration is associated with a form of synaptic plasticity at excitatory synapses formed onto VTA DA neurons which is disrupted in the mutant mice. Loss of neuroligin-3 also results in a disruption of translation homeostasis – providing an unexpected link between synaptic adhesion and signaling to mRNA translation. In collaboration with Dr. Kassoum Nacro, a medicinal chemist at the Experimental Therapeutics Centre in Singapore we are working on the development of pharmacological interventions that would normalize neuronal plasticity in VTA dopaminergic neurons and restore social recognition in mice. The long-term goal is to identify preclinical candidate small molecules that could be advanced to clinical studies. This work emerged from EU-AIMS, a major Innovative Medicines Initiative project supported by the European Union, and as further advanced under the EU-funded project AIMS-2-TRIALS.