Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior

Abstract

Summary Modulation of corticostriatal synaptic activity by dopamine is required for normal sensorimotor behaviors. After loss of nigrostriatal dopamine axons in Parkinson's disease, l-DOPA and dopamine D2-like receptor agonists are used as replacement therapy, although these drugs also trigger sensitized sensorimotor responses including dyskinesias and impulse control disorders. In mice, we lesioned dopamine projections to left dorsal striatum and assayed unilateral sensorimotor deficits with the corridor test as well as presynaptic corticostriatal activity with the synaptic vesicle probe, FM1-43. Sham-lesioned mice acquired food equivalently on both sides, while D2 receptor activation filtered the less active corticostriatal terminals, a response that required coincident co-activation of mGlu-R5 metabotropic glutamate and CB1 endocannabinoid receptors. Lesioned mice did not acquire food from their right, but overused that side following treatment with l-DOPA. Synaptic filtering on the lesioned side was abolished by either l-DOPA or a D2 receptor agonist, but when combined with a CB1 receptor antagonist, l-DOPA or D2 agonists normalized both synaptic filtering and behavior. Thus, high-pass filtering of corticostriatal synapses by the coordinated activation of D2, mGlu-R5, and CB1 receptors is required for normal sensorimotor response to environmental cues.

Dopamine’s Effects on Corticostriatal Synapses during Reward-Based Behaviors

“…A clue is that presynaptic imaging experiments conducted in dopamine-deficient mice showed that corticostriatal filtering was absent under dopamine-depleted conditions, and that every presynaptic cortical input was inhibited by either dopamine or D2R stimulation (Bamford et al, 2004). This mechanism is supported by similar experiments in parkinsonian mouse models, which display disrupted synaptic filtering, dopamine receptor hypersensitivity and poor abilities on cognitive tests and with motor learning (Zhou and Palmiter, 1995; Bamford et al, 2004; Darvas and Palmiter, 2009, 2011; Wong et al, 2015).…”

“…Whether the effects on cell firing were due to pre- or post-synaptic sites could not be distinguished. However, work discussed below suggests that the dopamine acts mostly at D2R on SPNs, but the subsequent reduction in D2R-SPN neuronal activity arise from activation of a retrograde signal from the SPNs that activates presynaptic cannabinoid receptors and inhibits glutamate release from cortical inputs (Wang et al, 2012; Wong et al, 2015).…”

“…When endocannabinoid receptors were inhibited, the dopamine-dependent, high-pass filtering of cortical inputs was blocked. Further investigation showed that the source of endocannabinoid release was likely the indirect pathway SPNs and required activation of both extrasynaptic SPN D2R and group 1 mGLU receptors (Kreitzer and Malenka, 2005; Wang et al, 2012; Wong et al, 2015).…”

Corticostriatal plasticity in the nucleus accumbens core

“…Although paired‐pulse facilitation can also be generated by changes in postsynaptic receptors (Kirischuk et al, ), the results are similar to the presynaptic depression found in the dorsal striatum following contingent and non‐contingent use of methamphetamine (Bamford et al, ) and amphetamine (Storey et al, ; Wang et al, ). The observed depression was not due to current spread, because (a) eEPSCs in SPNs required intact corticostriatal axons, (b) the resting membrane potential of SPNs was unchanged by cortical stimulation, and (c) similar methods produced opposing responses in saline‐treated controls (Wong et al, ).…”

“…Once the PFC becomes active, dopamine provides a frequency‐dependent suppression of corticoaccumbal boutons with a low probability of release. This filtering of cortical information by dopamine may then act to suppress extraneous information and provide a mechanism whereby the animal might focus attention on meaningful and relative information that leads to rewarding behaviors (Bamford & Bamford, ; Bamford, Zhang, et al, ; Bamford et al, ; Wong et al, ). A similar filtering mechanism by dopamine has been described in the dorsal striatum (Bamford, Zhang, et al, ) and has been more fully described within the NAc core (Wang et al, ).…”