Neuronal circuit assembly and synapse formation
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.
Coupling of postsynaptic neurotransmitter complexes to synaptic adhesion molecules
Synaptic adhesion molecules have important roles in organizing synaptic structures. In the past years we have focused on one pair of synaptic adhesion molecules called the neuroligin-neurexin complex which spans the synapse and contributes to the organization of pre- and postsynaptic membrane compartments. In cell biological studies we identified a novel mode of lateral coupling between neuroligins and neurotransmitter receptors in the postsynaptic membrane. We demonstrated that neuroligin-1 recruits NMDA-type glutamate receptors through interactions via the extracellular domains of the protein. These interactions are critical for physical retention of a pool of NMDA-receptors at glutamatergic synapses in vivo and regulate NMDA-receptor-dependent synaptic plasticity in the mouse hippocampus (Budreck et al., PNAS, 2013). These findings highlight the possibility that neurotransmitter receptors and adhesion molecules assemble into complexes that have structural roles at central synapses.
Molecular diversification of recognition molecules by alternative splicing
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. Therefore, highly polymorphic cell surface receptor families arising from extensive alternative splicing provide attractive candidates for neuronal recognition. Neurexins are highly polymorphic synaptic cell surface receptors that are extensively modified by alternative splicing. Alternative splice variants of neurexins differ in biochemical interactions with neuroligins and other binding partners and may underlie an adhesive code at central synapses. We discovered that neurexin alternative splicing is regulated by neuronal activity. The KH-domain RNA-binding protein SAM68 binds directly to the neurexin-1 pre-mRNA and is essential for activity-dependent splicing regulation (Iijima et al., Cell, 2011). SAM68-like proteins (SLM1 and SLM2) exhibit highly selective expression patterns in interneuron populations in the mouse brain. These findings provide an entry point to unraveling the cell type-specific neurexin repertoires and their contribution to neuronal connectivity.
Synaptic defects in autism-spectrum disorders
Autism-spectrum disorders are amongst the most heritable neurodevelopmental disorders known to date. Human genetic studies conducted over the past 10 years have led to the identification of several candidate genes that may confer susceptibility to autism but also environmental risk factors might exist. The study of neuronal circuit alterations in autism has been most advanced for monogenic forms of syndromic autism, such as Fragile X and Rett’s Syndrome, where specific alterations in synaptic transmission have been identified. We focused our studies on a mouse model of a non-syndromic form of autism, carrying a mutation in the synaptic adhesion molecule neuroligin-3. Using a combination of electrophysiological, anatomical, and behavioral studies we identified a remarkable convergence in the synaptic pathophysiology in neuroligin-3 knock-out mice and a rodent model of Fragile X, characterized by a defect in metabotropic glutamate receptor-dependent synaptic plasticity. Importantly, the synaptic defects could be reversed by re-expression of neuroligin-3 in adult animals highlighting a substantial reversibility of the neuronal phenotypes in this model (Baudouin et al., Science, 2012). In ongoing studies we are now testing pharmacological interventions in transgenic mouse and rat models of autism to identify treatment strategies for the disorder.
Emergence of synaptic specificity in the pontocerebellar projection system
A key question in neural development is how axons choose their appropriate synaptic partners. We performed a detailed anatomical analysis to unravel how target specificity of ponto-cerebellar mossy fiber projections emerges during development. We observed that mossy fibers form transient synapses with Purkinje cells (an “inappropriate target”) before precise connectivity with granule cells is established. We discovered that Purkinje cell-derived bone morphogenetic protein 4 (BMP4) acts as a retrograde signal that drives the destabilization of mossy fiber contacts (Kalinovsky et al., PLoS Biology, 2011). Interestingly, the bone morphogenetic protein signaling pathway continues to be active in the adult cerebellum. Therefore, we are now examining functions of this signaling system in learning-dependent plasticity in mature cerebellar circuits.