All mammalian behavior relies on the recruitment of neuronal ensembles into precisely orchestrated discharges. How the different cellular and synaptic elements of a neuronal ensemble cooperate to produce characteristic patterns of activity in the central nervous system is a fundamental and important question in neuroscience. Resolving the function of elementary synaptic microcircuits that form a more complex circuitry will therefore significantly advance our understanding of brain function.
On the level of individual nerve cells, understanding how complex temporal and spatial input patterns from excitatory, inhibitory and modulatory synapses are integrated to form an output signal is essential to grasp their function in the context of neuronal networks. To examine integration on the level of single cells, we are combining electrophysiology with multiphoton imaging and photostimulation techniques (Remy et al., 2009; Krueppel et al., 2011; Müller et al., 2012; Thome et al., 2014). Together with our collaborators, we are developing novel tools for selective neuronal manipulation such as aptamers (Lennarz et al., 2015), novel caged compounds, and optogenetic tools. On the level of networks, we are applying optogenetics, in-vitro and in-vivo patch-clamp recording, and dual-color in-vivo multiphoton imaging and fiber-optometry to understand how modulatory and inhibitory circuits structure input-output properties of specific neuronal subregions.
CNS Disorders and Epilepsy
In the context of CNS disorders, such as epilepsy, we believe that a profound understanding of normal brain function is also essential for understanding the pathophysiology of CNS disorders. Specifically, we are addressing the following questions:
- What are the key network motifs important in temporal lobe epilepsy? We are applying the abovementioned approaches to study changes in specific temporal lobe connectivity motifs in models of epilepsy.
- What are the mechanisms of pharmacoresistance? We have identified a decreased use-dependent block of sodium channels as a potential key mechanism of pharmacoresistance in patients with epilepsy to classical sodium channel blocking anticonvulsants (Remy et al., 2003;Remy and Beck, 2006). This resistance mechanism seems to be overcome by novel anticonvulsant drugs like eslicarbazepine (Doeser et al., 2015)
- What are the network mechanisms of anticonvulsants? For many CNS drugs, molecular targets are known (i.e. sodium channels or GABA receptors). Suprisingly, however, a precise knowledge of how they act on the different constituent parts of neuronal networks is largely absent. We are examining how anticonvulsants act on interneurons and principal neurons, and how they affect canonical neuronal motifs (Pothmann et al., 2014).