Dichotomous dopaminergic control of striatal synaptic plasticity - PubMed (original) (raw)

Dichotomous dopaminergic control of striatal synaptic plasticity

Weixing Shen et al. Science. 2008.

Abstract

At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively-forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

D2 MSNs displayed bidirectional Hebbian STDP dependent upon D2 and A2a receptors. (A) Schematic illustration of the recording/stimulation configuration. (B) The theta-burst pairing protocols for induction of LTP and (C) LTD. (B and C) Scale bars: 40 mV × 200 ms. (D) LTP induced in by a positive timing pairing. Plots show EPSP amplitude and input resistance as a function of time. The dashed line shows the average EPSP amplitude before induction. The induction was performed at the vertical bar. Filled symbol shows the averages of 12 trials (± s.e.m.). The averaged EPSP traces before and after induction are showed at the top. Scale bars: 2 mV × 100 ms. (E) LTD induced by a negative timing pairing. Plots and EPSP traces as in (D). Scale bars: 2 mV × 100 ms. (F) In the presence of D2 receptor antagonist sulpiride (10 μM), negative timing pairing failed to alter EPSP amplitude. But co-application of A2a adenosine receptor agonist CGS 21680 (100 nM) and sulpiride led to LTP (n = 6; P < 0.05, Wilcoxon). G) LTP induction (n = 11; P < 0.01, Wilcoxon) was disrupted by the NMDA receptor antagonists APV (50 μM) and MK-801 (20 μM) or the A2a receptor antagonist SCH58261 (100 nM). (H) In the presence of D2 receptor agonist quinpirole (10 μM, n = 6), the application of the positive timing protocol leads to induction of LTD. Application of quinpirole and CGS21680 (100 nM, n = 6) together restored LTP with a positive timing pairing. (I) Schematic illustration shows that activation of A2a and NMDA receptors leads to LTP and activation of D2 and mGluR5 receptors and CaV1.3 channels leads to LTD. Moreover, A2a and D2 receptor activation opposes each other in inducing plasticity. Glu, glutamate; EC, endocannabinoid.

Fig. 2

Fig. 2

D1 MSNs displayed bidirectional Hebbian STDP dependent upon D1 receptors. (A) LTP induction by a positive timing pairing protocol. EPSP amplitude and input resistance of the recorded cell were plotted as a function of time. The averaged EPSP traces before and after induction are shown at the top. Scale bars: 2 mV × 100 ms. (B) LTP induction (n = 10; P < 0.01, Wilcoxon test) was blocked by APV (50 μM) and MK-801 (20 μM). (C) LTD was not induced in D1 neurons with a negative pairing. Plots and EPSP traces are from a single cell as in (A). Scale bars: 2 mV × 100 ms. (D) In the presence of D1 receptor antagonist SCH23390 (3 μM), a negative timing pairing revealed LTD. But in the presence of CB1 receptor antagonist AM-251 (2 μM), negative pairing failed to alter EPSP amplitude. (E) LTP induced by a positive timing pairing was blocked by SCH23390, revealing LTD. LTD induced in the presence of SCH23390 was disrupted by AM-251. (F) Schematic drawing shows that activation of D1 and NMDA receptors evokes LTP and activation of mGluR5 receptor and CaV1.3 channels evokes LTD. Moreover, D1 and mGluR5 receptor activation opposes each other in inducing plasticity.

Fig. 3

Fig. 3

Bidirectional Hebbian STDP is disrupted in MSNs from parkinsonian mice. (A) Light microscopic image of a coronal section showing the loss of immunoreactivity for TH following unilateral 6-OHDA lesioning. Cx, cortex; CPu, caudate putamen. (B) LTP was induced from lesioned D2 mice and (C) reserpine treated mice following a positive timing protocol. Plot of average EPSP amplitude as a function of time. In (C), timing-dependent LTP induced in reserpine treated animals was blocked by SCH58261 (100 nM). (D) LTP also was induced with a negative timing protocol that would normally induce LTD. In contrast, perfusion of quinpirole (10 μM) restored LTD. (E) timing-dependent LTD was evoked in D1 MSNs from lesioned D1 mice and (F) reserpine-treated mice. In (F), D1 receptor agonist SKF81297 (3 μM) restored LTP following a positive timing protocol. The LTD induced in reserpine-treated mice was disrupted by AM-251 (2 μM).

Similar articles

Cited by

References

    1. Graybiel AM, Aosaki T, Flaherty AW, Kimura M. Science. 1994;265:1826. - PubMed
    1. Yin HH, Knowlton BJ. Nat Rev Neurosci. 2006;7:464. - PubMed
    1. Reynolds JN, Hyland BI, Wickens JR. Nature. 2001;413:67. - PubMed
    1. Schultz W. J Neurophysiol. 1998;80:1. - PubMed
    1. Surmeier DJ, Ding J, Day M, Wang Z, Shen W. Trends Neurosci. 2007;30:228. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources