Dopaminergic Modulation of Corticostriatal Responses in Medium Spiny Projection Neurons from Direct and Indirect Pathways

Suprathreshold corticostriatal responses recorded from medium spiny neurons (MSNs) from the direct and indirect pathways of the basal ganglia are different. Their differences readily distinguish D1- and D2-type receptor expressing MSNs in both bacterial artificial chromosome-transgenic mice and their control littermates as well as in rats: indirect pathway neurons are more excitable than direct pathway neurons revealing autoregenerative spikes underlying their spike trains, whereas direct pathway neurons exhibit more prolonged plateau potentials and spike trains. SFK 81297, a selective agonist for D1-class receptors enhanced corticostriatal responses in direct pathway neurons, while quinelorane, a selective agonist for D2-class receptors reduced orthodromic and autoregenerative responses in indirect pathway neurons thus making both neuron classes similarly excitable. Because dopaminergic postsynaptic actions target CaV1 (L) class voltage-gated calcium channels in MSNs, we hypothesized that these channels are involved and can explain a part of the dopaminergic actions on corticostriatal integration. Both 2.5 μM nicardipine and 400 nM calciseptine, selective CaV1 channel blockers, reduced corticostriatal responses in both D1- and D2-receptor expressing neurons, respectively. A previous blockade of CaV1 channels occluded the actions of dopamine agonists in both neuronal classes. In contrast, a CaV1 (L) channel activator, 2.5 μM Bay K 8644, enhanced corticostriatal responses in neurons from both pathways. It is concluded that CaV1 intrinsic currents mediate a part of the dopaminergic modulation during orthodromic synaptic integration of cortical inputs in both classes of MSNs

Different Corticostriatal Integration in Spiny Projection Neurons from Direct and Indirect Pathways

The striatum is the principal input structure of the basal ganglia. Major glutamatergic afferents to the striatum come from the cerebral cortex and make monosynaptic contacts with medium spiny projection neurons (MSNs) and interneurons. Also: glutamatergic afferents to the striatum come from the thalamus. Despite differences in axonal projections, dopamine (DA) receptors expression and differences in excitability between MSNs from “direct” and “indirect” basal ganglia pathways, these neuronal classes have been thought as electrophysiologically very similar. Based on work with bacterial artificial chromosome (BAC) transgenic mice, here it is shown that corticostriatal responses in D1- and D2-receptor expressing MSNs (D1- and D2-MSNs) are radically different so as to establish an electrophysiological footprint that readily differentiates between them. Experiments in BAC mice allowed us to predict, with high probability (P > 0.9), in rats or non-BAC mice, whether a recorded neuron, from rat or mouse, was going to be substance P or enkephalin (ENK) immunoreactive. Responses are more prolonged and evoke more action potentials in D1-MSNs, while they are briefer and exhibit intrinsic autoregenerative responses in D2-MSNs. A main cause for these differences was the interaction of intrinsic properties with the inhibitory contribution in each response. Inhibition always depressed corticostriatal depolarization in D2-MSNs, while it helped in sustaining prolonged depolarizations in D1-MSNs, in spite of depressing early discharge. Corticostriatal responses changed dramatically after striatal DA depletion in 6-hydroxy-dopamine (6-OHDA) lesioned animals: a response reduction was seen in substance P (SP)+ MSNs whereas an enhanced response was seen in ENK+ MSNs. The end result was that differences in the responses were greatly diminished after DA depletion