Title: Dopamine Modulates Corticostriatal Inputs During Motor Command Signalilng
Description: Normal motor signaling in the basal ganglia requires regulating which movements to suppress and which to enact. In Parkinson's disease, loss of dopamine levels due to loss of dopaminergic neurons results in unbalanced basal ganglia output and loss of motor control. Motor sequences are thought to be triggered by cortical inputs as these glutamatergic inputs provide the main excitatory drive to the striatal output neurons. Dopamine is a crucial modulator of corticostriatal activity and loss of its normal function plays an important role in the pathophysiology of Parkinson's disease. We hypothesize that the functional reorganization of the cortical inputs to the striatum following long-term dopamine depletion as well as the response to dopamine replacement therapies has important functional implications in the pathogenesis and treatment of Parkinson's disease motor symptoms. To address this hypothesis, we adapted an optical technique using lipophilic dye, FM 1-43, to characterize the activities of the two major classes of corticostriatal projection neurons - the ipsilateral and contralateral cortical projections - and compared the influence of dopamine D2 receptors on these inputs.

We found that both cortical projections shared similar patterns of terminal release and were both inhibited by D2 receptor activation. A D2 receptor-mediated inhibition specifically targeted the least active (slow-releasing) corticostriatal inputs with low probability of release. This "filtering" effect by D2 receptors confirmed a role for dopamine in modulating excitatory cortical inputs that could be crucial to selection of proper motor functions. To study the loss of motor control during conditions of chronic dopamine depletion, we employed a classic Parkinson's disease rodent model in which dopamine is depleted from one hemisphere using the neurotoxin, 6-hydroxydopamine. Behavior tests confirmed lateralized motor response due to loss of function in the forelimb contralateral to the side of lesion. The effect of chronic dopamine depletion on corticostriatal synaptic activity was assessed by comparing the activity between the dopamine-intact and dopamine-lesioned hemispheres. We proposed that in the dopamine-intact hemisphere, D2 receptor activation exerted selective inhibitory influence or "filtering" on corticostriatal signaling through two mechanisms: presynaptic D2 receptors directly inhibiting glutamate release and postsynaptic D2 receptor-mediated retrograde endocannabinoid inhibition activating presynaptic CB1 receptors.

However, in the dopamine-lesioned hemisphere, there was a supersensitive inhibition by D2 receptor activation and the "filtering" effect was lost: the "filtering" was partially restored by concurrently activating D2 receptors and inhibiting CB1 receptors. We then tested whether this endocannabinoid-mediated restoration of D2 receptor "filtering" in corticostriatal inputs had an effect on motor function in vivo. We examined changes in motor function and corticostriatal activity in 6-OHDA lesioned mice following DA replacement therapy with L-DOPA in combination with modulators of endocannabinoid transmission. We found that treatment with L-DOPA alone or with L-DOPA + URB597 (an inhibitor of endocannabinoid breakdown) reduced contralateral akinesia and in fact led to a contralateral limb use preference. Following L-DOPA treatment, corticostriatal presynaptic activity was depressed in the lesioned striata and D2 receptor-mediated inhibition was occluded. Treatment of L-DOPA with the CB1 receptor antagonist, AM251, completely normalized motor function.

This treatment regime also completely normalized basal corticostriatal activity on the lesioned hemisphere, and the D2 receptor "filtering" effect was restored. Our findings confirm that dopamine modulates excitatory corticostriatal activity presynaptically via D2 receptor activation, a portion of which is due to cannabinoid effects. Furthermore, a correlation between dopamine-induced loss of motor function and loss of corticostriatal "filtering" by D2 receptors was demonstrated by the fact that dopamine replacement treatment that restores behavior also preserves this "filtering" mechanism in corticostriatal inputs. These findings suggest that dopaminergic "filtering" of particular corticostriatal synaptic activity contributes to motor commands.