Neuromodulation shapes interneuron communication in the mouse striatum

Abstract: A proper understanding of cognition relies on detailed knowledge about the functional connectivity within and between brain areas. The striatum is generally regarded as the input structure to the basal ganglia, a group of subcortical nuclei that have been demonstrated to be involved in motor function and reward, amongst other functions. This becomes especially evident under pathological conditions such as Parkinson’s disease, when impaired motor function arises from reduced dopaminergic innervation of the striatum. These symptoms can be partially explained by the divergent effect dopamine exerts on the excitability of striatal projection neurons. However, less is known about its modulatory effects on striatal interneurons and the physiological outcomes of altered interneuron communication. Through a combination of ex vivo patch-clamp electrophysiology, in vivo extracellular recordings and transgenic labelling of specific interneuron populations, we probed interneuron communication in the striatum under normal and dopamine-depleted conditions. Furthermore, through opto- and chemogenetic manipulation we investigated how various neurotransmitters alter neuronal communication and how this affects the activity of the striatal projection neurons. In study 1 we investigate the differential inhibition of striatal projection neurons by subpopulations of parvalbumin-expressing interneurons. Subpopulations of these interneurons are characterized by their selective co-expression of the calcium-binding protein secretagogin. Interneurons co-expressing secretagogin are heterogeneously distributed and preferentially inhibit projection neurons of the direct pathway. Conversely, parvalbumin-expressing interneurons negative for secretagogin are more homogeneously distributed throughout the striatum and are biased towards indirect-pathway projection neurons. The ability of dopamine to elicit spiking was investigated computationally in study 2. Dopamine induced depolarizations in direct-pathway projection neurons, in particular through down-regulating the Kv4.2 potassium channel. However, these effects alone are insufficient to explain the fast firing onset following dopamine release observed experimentally. Further modulation of striatal projection neurons may be enacted through co-release of other neurotransmitters. In study 3 we demonstrate glutamate co-release from midbrain dopamine neurons onto D1-receptor expressing projection neurons in the Nucleus Accumbens. A conditional Vglut2-knock-out mouse model was developed to target mature dopamine neurons, which isolates these effects from compensatory mechanisms during development. We thus demonstrated that Vglut2-mediated glutamate transmission from mature dopamine neurons modulates baseline AMPA/NMDA ratios. This highlights the role of glutamate co-release in synaptic plasticity, especially in relation to drug addiction. Midbrain dopamine neurons play a further role in modulating interneuron communication in the dorsal striatum. In study 4 we demonstrate that dopamine, acting on D2 receptors, inhibits polysynaptic communication between cholinergic interneurons in the dorsal striatum. This polysynaptic inhibition between cholinergic interneurons is partially mediated by gabaergic interneurons co-expressing the enzyme tyrosine hydroxylase. We also report gabaergic innervation on striatal cholinergic interneurons from dopaminergic and gabaergic projection neurons in the ventral tegmental area and the substantia nigra pars compacta, potentially providing additional connectivity and methods of control between the striatal dopamine and acetylcholine systems. In study 5 we subsequently modelled many of these interactions in a detailed striatal model which receives realistic input from the cortex, thalamus and dopamine system. By modelling interactions between striatal interneurons and projection neurons we are able to provide a substrate for detailed investigations into striatal dynamics. Through multi-compartmental neuron models which closely match their biological counterparts we are able to investigate network effects on an unprecedented level. We have made this model publically available so it may be freely augmented and adjusted where necessary to study different aspects of striatal function. By identifying selective pathways of innervation within and into the striatal network, we are now better able to understand how disrupting these pathways affects striatal function. In particular the role of dopamine and how it modulates striatal output has been revised in these studies. This has important ramifications for how we can interpret the physiological changes observed in altered dopaminergic states, such as those found in patients with Parkinson’s disease. Going forward, our results highlight the necessity for a detailed map of the striatal microcircuit in general and particularly how the microcircuit is affected by the neuromodulators that underlie striatal function on both shorter and longer time-scales.