The retina consists of six principal cell types that are generated in a chronological sequence from retinal progenitor cells in during eye development. These different cell types can be further divided into specific subclasses that are spread across the retina, generating more than 60 different retinal cell subtypes. Subclass-specific circuits are present to separate visual information into separate channels, such as orientation, movement, light intensity etc. A feature of such individual circuits, for example between retinal ganglion cells (RGCs) and their presynaptic partners, the bipolar or amacrine cells, is the organisation of their synaptic interactions in precise vertical stacks in the inner plexiform layer (IPL) of the retina. However, the molecular mechanisms underlying the formation of these precise synaptic connections are still not fully understood. We have identified a family of synaptic adhesion molecules that are expressed by different subtypes of RGCs and amacrine cells. Furthermore, our recent results show that a loss of function for members of this gene family (via CRISPR/Cas9 and TALEN technology) leads to specific structural defects in the retinal wiring, suggesting a role for these adhesion molecules in the assembly of these specific circuits. We are now working to dissect the roles of additional synaptic molecules during the establishment of the visual circuitry.
Visual information is pre-processed in the retina and split into a number of different parallel functional channels before being relayed to the brain proper. However, it is still unclear, how many such different channels exist and what exactly they encode. Based on our structural identification of different retinal cell subtypes and their specific connectivity, we are interested to functionally characterise the circuits they belong to. For this, we perform in vivo functional imaging in the retina and the brain of zebrafish larvae using genetically encoded calcium indicators (GCaMPs), expressed in different neuronal populations. Our recent studies have identified genes that are important for the generation of an “orientation selective” visual circuit. Cells belonging to this circuit filter out visual stimuli that are oriented along a particular orientation in the visual field (but not any other orientation) and relay this information to the brain. In humans, for example, this functionality is important to identify visual features during face recognition. We are currently characterising additional functional circuits that are marked by and possibly formed with the help of different synaptic adhesion molecules.
Topographic maps are a fundamental organisational feature of most axonal connections in the brain. The dominant model for studying map development is the projection from the eye to the midbrain target, the superior colliculus in mammals or their non-mammalian homologue, the optic tectum. The precise spatial ordering of axonal arborizations of retinal ganglion cells (RGCs) maps the visual world along two sets of orthogonally oriented axes: the temporal-nasal axis of the retina along the anterior-posterior axis of the colliculus, and the dorsal-ventral retinal axis along the lateral-medial collicular axis. Recent findings from several labs, including ours, indicate that in addition to molecular cues and activity-dependent mechanisms, other factors, such as axon-axon competition or cell density play an important role to shape the final map formation. However, their exact contribution is still unclear. Using a combination of mouse genetics, neuronal tracing and behavioural approaches, we are currently investigating how for example changes in cell density alter the organisation of a topographic map at the levels of structural connectivity and also functional readout.
One of the most remarkable features of neural development is the specificity of synapse formation. In order to ensure that the correct pre- and postsynaptic partners find each other at the correct place and time and form the right type of functional synapse, a precise series of events, including cell type specification, cell migration, axon guidance, synaptic target selection and synaptogenesis, have to be implemented. How this complicated program is orchestrated during development is still one of the major questions in neuroscience. We are currently focusing on the Teneurin family of synaptic adhesion molecules and their interaction partners to investigate their function for synapse formation during development, but also as regulators for synapse maintenance in later stages of life. For this we are using in vivo (mouse genetics) and in vitro (organotypic and dissociated hippocampal cultures) approaches, combined with viral tracing and imaging technologies. Mutations in some of our candidate molecules have been genetically linked with several neurological disorders, including mental retardation, bipolar disorder, epilepsy and spinocerebellar ataxia. We therefore believe that our results on the fundamental molecular mechanisms will have an impact on the understanding of the aetiology of these disorders.