Dissociable effects of dopamine on neuronal firing rate and synchrony in the dorsal striatum

Abstract

Previous studies showed that dopamine depletion leads to both changes in firing rate and in neuronal synchrony in the basal ganglia. Since dopamine D1 and D2 receptors are preferentially expressed in striatonigral and striatopallidal medium spiny neurons, respectively, we investigated the relative contribution of lack of D1 and/or D2-type receptor activation to the changes in striatal firing rate and synchrony observed after dopamine depletion. Similar to what was observed after dopamine depletion, co-administration of D1 and D2 antagonists to mice chronically implanted with multielectrode arrays in the striatum caused significant changes in firing rate, power of the local field potential (LFP) oscillations, and synchrony measured by the entrainment of neurons to striatal local field potentials. However, although blockade of either D1 or D2 type receptors produced similarly severe akinesia, the effects on neural activity differed. Blockade of D2 receptors affected the firing rate of medium spiny neurons and the power of the LFP oscillations substantially, but it did not affect synchrony to the same extent. In contrast, D1 blockade affected synchrony dramatically, but had less substantial effects on firing rate and LFP power. Furthermore, there was no consistent relation between neurons changing firing rate and changing LFP entrainment after dopamine blockade. Our results suggest that the changes in rate and entrainment to the LFP observed in medium spiny neurons after dopamine depletion are somewhat dissociable, and that lack of D1- or D2-type receptor activation can exert independent yet interactive pathological effects during the progression of Parkinson's disease.

Keywords: Parkinson's disease; caudate; entrainment; local field potentials; movement; oscillations; putamen.

Figure 1

Effect of dopamine receptor blockade on spontaneous locomotion. (A) D1 + D2 antagonist. (B) D1 antagonist. (C) D2 antagonist. All treatments significantly reduced spontaneous locomotion in comparison to saline injection. Effect of combined D1 + D2 antagonist treatment was significantly greater than either D1 antagonist alone or D2 antagonist alone.

Figure 2

(A) Example of a sorted single unit, recorded 2 weeks subsequent to electrode implantation. From left: unit waveforms (yellow) isolated from noise (gray) (x-axis, 800 μs; y-axis, 120 μV); interspike interval histogram; isolated unit and noise on a principle component plot (x-axis, PC1; y-axis, PC2); bottom, raster trace of unit events and noise events over a selected time period. (B,C) Sorting criteria for identifying putative medium spiny neurons (MSNs), fast-spiking interneurons (FSIs), and large aspiny neurons (LANs). (B) Criteria used for identifying putative neuron types were half-width (x-axis), firing rate (y-axis), and amplitude (z-axis). (C) Representative waveforms. Top panel (in red) depicts a putative FSI. Middle panel (in blue) depicts a putative MSN. Bottom panel (in black) depicts a putative LAN.

Figure 3

Examples of firing rate change in single neurons. Single neurons showing increase (left column) and decrease (center column) in firing rate were observed after all treatment conditions. Neurons displaying no significant change in rate were also observed (right column). (A–C) Saline injection. (D–F) D1 + D2 antagonist injection. (G–I) D1 antagonist injection. (J–L) D2 antagonist injection.

Figure 4

Effect of dopamine receptor blockade on neuronal firing rate. (A) Percentage of total neurons showing a significant change in firing rate after treatment. After D1 + D2 and D2 receptor blockade more neurons changed firing rate than after saline injection. (B) Proportion of the neurons that changed firing rate showing increase in firing rate versus decrease in firing rate. With saline injection the proportion of neurons showing rate increase versus decrease was equivalent to each other. With all dopamine receptor antagonist treatments, significantly more neurons showed decrease in firing rate (∼80%) than increase in rate.

Figure 5

(A–D) Examples of LFP power spectra and corresponding power spectrum index for different treatments throughout the time course of the experiment. Arrow indicates the time of injection. (E) Summary of the effect of dopamine receptor blockade on power spectrum index. D1 + D2 antagonist and D2 antagonist caused a significant decrease in power spectrum index after injection.

Figure 6

(A–D) Representative spike-triggered average histograms. (A) An MSN shows no significant entrainment to the LFP in the baseline state, but develops a pronounced entrainment to the trough of the LFP oscillation subsequent to DA receptor blockade. (B) An MSN showing no entrainment to the LFP continues to show no entrainment after saline injection. (C) An FSI shows some entrainment to the LFP peak in the pre-injection state, with a substantial increase in entrainment post-injection. (D) A LAN shows significant entrainment to the LFP trough in both pre- and post-injection. (E) D1 + D2 antagonists and D1 antagonist alone resulted in a significant increase in the percentage of neurons showing entrainment to the LFP oscillation post-injection, while D2 antagonist alone and saline produced no significant changes.

Figure 7

Probability of changing entrainment to the LFP for neurons changing or not changing firing rate after DA-blockade. Across all treatment conditions there was no difference in the probability of changing entrainment to the LFP between neurons that changed firing rate versus neurons that did not change firing rate after DA-blockade.