An indirect route to repetitive actions (original) (raw)
Wang and coworkers used mice expressing genetically encoded fluorescent proteins to identify direct and indirect pathway MSNs in brain slices taken from mice lacking the SHANK3 protein (9). Compared with those in control animals, glutamatergic synapses in _Shank3_-deficient mice showed decreased transmission in the indirect pathway MSNs, with no change in the synapses on direct pathway neurons. The authors also examined long-lasting changes in transmission at these glutamatergic synapses. Long-term depression (LTD) of synaptic transmission depends on activation of metabotropic glutamate receptors 1 and 5 (mGluR1 and mGluR5), L-type voltage gated calcium channels, and endocannabinoid activation of presynaptic cannabinoid 1 receptor (CB1R) (23). Wang and coworkers showed that LTD could not be induced in indirect pathway MSNs by afferent stimulation or pharmacological activation of mGluRs or calcium channels in the SHANK3-deficient mice. In contrast, LTD was intact after all procedures in WT mice and in direct pathway MSNs in Shank3 mutant mice. These results support previous work indicating that LTD can be induced at glutamatergic synapses onto MSNs that give rise to both pathways (24). These changes in synaptic function were accompanied by a decrease in the number of spines on the dendrites of indirect pathway MSNs, where glutamatergic synapses are made by cortical afferents. This finding suggests that the number of glutamatergic synapses onto indirect pathway MSNs is decreased in the mutant mice and that reduction of glutamatergic synapses could be a prominent mechanism underlying the decrease in synaptic transmission onto these projection neurons.
The reduction in glutamatergic synapses and synaptic transmission onto indirect pathway MSNs decreases excitation of these neurons in response to cortical (and perhaps thalamic) activity (Figure 1). The MSNs do not depolarize sufficiently to fire action potentials in the absence of coordinated glutamatergic synaptic transmission. Thus, decreasing the strength of this transmission would result in fewer indirect pathway MSNs being activated by bouts of glutamatergic input that occur during the initiation and performance of actions. When this effect is targeted primarily to indirect pathway MSNs, the net effect is a decrease in the striatal output to targets that normally reduce unwanted movements (25). Overall, the consequence of this circuit change would most likely be excessive production of certain actions. Such a mechanism could certainly contribute to the excessive bouts of grooming observed in SHANK3-deficient mice.
Decreased indirect pathway function in mice lacking the SHANK3 scaffolding protein. 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.
Indeed, Wang and coworkers demonstrated that activation of indirect pathway MSNs reduces excessive repetitive grooming in mice lacking Shank3. This was accomplished using a designer receptors exclusively activated by designer drugs (DREADD) approach, in which a clozapine-_N_-oxide–activated (CNO-activated) DREADD was specifically expressed in indirect pathway MSNs, resulting in increased MSN activity in mice given the drug. Reduced grooming was only seen in animals expressing DREADD in indirect pathway MSNs combined with drug treatment and not in CNO-treated animals that expressed DREADD in direct pathway MSNs. This finding supports the idea that abnormally strong indirect pathway activity contributes to excessive grooming in the mutant mice.
The loss of LTD observed in SHANK3-deficient mice provides another mechanism through which glutamatergic transmission may be altered, leading to deficient indirect pathway activation. This type of synaptic plasticity has been implicated in the learning of actions (23). Thus, a sustained deficit in plasticity at these synapses may signal loss of normal action learning, further contributing to excessive, repetitive behaviors.