Striatal microcircuitry and movement disorders

Abstract

The basal ganglia network serves to integrate information about context, actions, and outcomes to shape the behavior of an animal based on its past experience. Clinically, the basal ganglia receive the most attention for their role in movement disorders. Recent advances in technology have opened new avenues of research into the structure and function of basal ganglia circuits. One emerging theme is the importance of GABAergic interneurons in coordinating and regulating network function. Here, we discuss evidence that changes in striatal GABAergic microcircuits contribute to basal ganglia dysfunction in several movement disorders. Because interneurons are genetically and neurochemically unique from striatal projection neurons, they may provide promising therapeutic targets for the treatment of a variety of striatal-based disorders.

Figure 1

GABAergic microcircuits in the striatum. A. Schematic showing different classes of striatal neurons that contribute to local inhibitory networks. B. Illustration comparing the typical time course and amplitudes of unitary IPSCs (uIPSCs) observed in SPNs from each class of inhibitory neuron. FSIs typically synapse onto the somatic compartment of SPNs and produce large amplitude, fast kinetic responses in SPNs ^{, –}. PLTS interneurons are sparsely connected to SPNs and their synapses are found on the dendrites of SPNs . uIPSCs from PLTS interneurons are very small compared to those from FSIs, typically < 100 pA . A more important role for PLTS interneurons in regulating SPN function may be the release of neuromodulators such as NPY, SOM, and NO. TH-positive interneurons are similar electrophysiologically to PLTS interneurons. They also make inhibitory connections onto the distal dendrites of SPNs and produce small amplitude uIPSCs . The local release of dopamine by these neurons may be particularly important in diseases like PD, where the normally massive dopaminergic innervation of the striatum from the SNc is lost. NPY-NGF interneurons likely target the distal dendrites of SPNs ^, . Although NPY-NGF interneurons receive some excitatory inputs (presumably from both cortex and thalamus), they are also well activated by acetylcholine (ACh) release from striatal cholinergic interneurons . The uIPSCs from NPY-NGF interneurons have distinctive slow kinetics compared to uIPSCs from all other cell types ^, . Finally, SPNs also make lateral inhibitory connections with each other and these collateral synapses also target the dendritic compartments of SPNs ^, . Although the probability of finding a connection between any two SPNs is small and uIPSCs are weak, due to the large number of SPNs in the striatum relative to all other cell types (95% of striatal neurons are SPNs), this inhibitory collateral network may be a major source of local inhibition . Abbreviations: Chol, cholinergic interneuron; DA, dopamine.

Figure 2

Summary of changes in GABAergic microcircuits following dopamine depletion. A. Under normal conditions, SPNs laterally inhibit each other and inhibition is observed both across and within dSPN and iSPN subtypes . FSIs inhibit both dSPNs and iSPNs, but preferentially target dSPNs . PLTS interneurons release neuropeptides such as NPY and SOM and the neuromodulator NO which can modulate SPN activity . Under control conditions, inhibitory synapses from PLTS interneurons onto SPNs are hard to detect . The following changes have been observed to GABAergic microcircuits following pharmacological dopamine depletion in mice: B. Sprouting of FSI axons and the formation of new axons specifically onto iSPNs. This causes an inversion of the normal pathway-selectivity of FSIs such that after dopamine depletion, FSIs are more likely to target iSPNs than dSPNs . C. Reduction in connectivity and unitary strength of lateral inhibition between SPNs. Connections between dSPNs were sparse under control conditions and were no longer detected in dopamine depleted mice . D. An increase in the strength or connectivity of inhibitory inputs from PLTS interneurons onto SPNs may occur. This finding is based on increases in the frequency of large amplitude inhibitory postsynaptic currents (IPSCs) observed in SPNs after dopamine depletion , presumably arising from spontaneously active PLTS interneurons in the slice.