Who, when & how - Electrophysiological studies on Connectivity of Striatal Neurons

Abstract: The nervous system has been studied in many ways and in many different organisms. Organisms that have a brain and mind or a simpler nervous system use it to sense the environment, process this sensory input and make appropriate decisions on how to act or interact with the environment. The complexity of the nervous system varies with the type of organism but this basic function remains the same. This thesis aims to examine a part of the brain called the striatum that is tightly interlinked with action selection and motor control. The approach employed is a reductionist approach where we look at the different parts constituting the striatum, the striatal neuronal types (WHO), their interaction (HOW), temporal aspects of the interaction (WHEN) and by what means the interaction can be altered or modulated (HOW). In the first study we investigated the striatal neuronal types (WHO) and more specifically the histochemical and electrophysiological properties of the 5HT3a-EGFP + neurons. We showed that they are interneurons and show little overlap with any of the classical striatal markers with the highest overlap being with parvalbumin. Furthermore we have showed that they fall into three categories of interneurons with resemblance to the classical striatal interneurons Fast spiking interneurons (FSIs), neurogliaform interneurons (NGF) and Low-threshold spiking interneurons (LTSIs). The LTS-like 5HT3a-EGFP+ interneurons show a strong and reliable response to nicotine, which is different from the one recorded in LTSIs from Lhx6-EGFP mice. With the findings from the studies we hypothesize that the 5HT3a-EGFP+, LTSIs and NGF interneurons are a novel subpopulation of striatal interneurons. In the second study we investigated HOW the striatal neurons interact and the temporal aspects of this interaction (WHEN). More specifically we used the patch-clamp technique to investigate both intrastriatal feedforward and feedback connections and the dynamics of these synapses. We found that Medium spiny neuron to Medium spiny neuron (MSN) interconnectivity is sparse and that MSNs of both the indirect and direct pathway contact each other. The indirect pathway MSN is to a larger extent the presynaptic cell but contacts - MSNs of both types with similar probabilities. There is no difference in the connections when it comes to amplitudes or synaptic dynamics and they exhibit both facilitating and depressing components. We saw that FSIs contact MSNs with high probability and that these connections exhibit reliably depressing synaptic dynamics. Furthermore, they contact MSNs of both types and the same FSI even contacts MSNs of both types. In the third study we extended our investigations of feedforward inhibition by FSIs. We used optogenetics and patch-clamp recordings to investigate which striatal interneurons the FSIs form connections with. We found that FSIs are target selective and completely avoid Cholinergic interneurons (AChIs) while forming sparse connections with LTSIs. This suggests that the functions and roles of the different types of striatal interneurons are separated and that the AChIs could be specifically involved in reinforcement learning and that the FSIs have a more specific role in action-selection. In the last study we investigated HOW the striatal connections can be altered by membrane fluctuations. More specifically we investigated how the membrane potential of the presynaptic cell can modulate the connections formed between FSI-MSN and MSN-MSN. We found that it has an effect on the release probability of the synapse. The extent of the effect is dictated by the initial release probability of the synapse and this type of presynaptic modulation might serve to make synapses more precise and time-locked. The study indicates how the membrane potential fluctuations of striatal neurons seen in-vivo can alter the dynamics of the connectivity.