An indirect route to repetitive actions
David M. Lovinger
David M. Lovinger
Published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):1618-1621. https://doi.org/10.1172/JCI93918.
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Commentary

An indirect route to repetitive actions

Abstract

It is increasingly evident that there is a genetic contribution to autism spectrum disorders (ASDs) and other neural disorders involving excessive repetition of action sequences. Among the implicated genes in these disorders are those encoding postsynaptic scaffolding proteins with roles in synaptic transmission and plasticity. Several mouse models harboring synonymous mutations have shown alterations in synaptic transmission within the striatum, which has key roles in controlling actions and action sequences. In this issue of the JCI, Wang and coworkers show that glutamatergic synaptic transmission onto striatal projection neurons is weakened in mutant mice lacking the SH3 and multiple ankyrin repeat domains 3 (SHANK3B) scaffolding protein, defective expression of which has been implicated in ASDs. This synaptic alteration gives rise to stronger activity in the indirect pathway accompanied by decreased dendritic spines on the indirect pathway medium spiny projection neuron, indicative of decreased numbers of glutamatergic synapses. Selectively enhancing activity in this pathway reduced excessive repetitive grooming in the mutant mice. Changes in glutamatergic input to striatal projection neurons have been observed in several other murine ASD models and associated disorders. Thus, manipulation of the function of the striatal indirect pathway may be a useful therapeutic target for treating disorders characterized by excessive repetitive behaviors.

Authors

David M. Lovinger

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Figure 1

Decreased indirect pathway function in mice lacking the SHANK3 scaffolding protein.

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Decreased indirect pathway function in mice lacking the SHANK3 scaffoldi...
Schematic diagrams of the cortico–basal ganglia direct and indirect pathways in WT mice and mice lacking the SHANK3 postsynaptic scaffolding protein. In WT mice, cortical synaptic input to direct and indirect pathway MSNs helps to keep the appropriate balance of striatal output that determines which actions are allowed and which are suppressed. In mice lacking SHANKB, cortical input to indirect pathway MSNs is weakened, resulting in less synaptic excitation of these neurons and less GABAergic inhibitory output to the globus pallidus external segment (GPe). This results in greater GABAergic inhibition of GPe output to the substantia nigra pars reticulata (SNr), thus suppressing basal ganglia output. The net result of these circuit changes is impaired suppression of unwanted actions, excessive grooming in particular.