Long-term modification of synaptic transmission at corticostriatal synapses is implicated in voluntary motor control, reward-based learning, and habit formation (Reynolds and Wickens, 2002; Yin and Knowlton, 2006). Unlike many excitatory synapses in the brain that are potentiated by high-frequency afferent stimulation, repeated activation of glutamatergic afferents in the presence of tonic levels of dopamine induces long-term depression (HFS-LTD) of synapses on medium spiny neurons (MSNs) in the dorsolateral striatum. HFS-LTD requires dopamine D2 receptor activation, high levels of intracellular calcium, and retrograde release of endocannabinoids that activate presynaptic CB1 receptors. A recent study by Adermark and Lovinger (2007) in The Journal of Neuroscience provides strong evidence that activation of L-type calcium channels may be the molecular switch in this signaling pathway, bypassing dopamine-dependent mechanisms to induce corticostriatal LTD (Fig. 1).
In their first experiment, Adermark and Lovinger (2007) show that LTD can be induced with only modest presynaptic activity and modest postsynaptic depolarization if there is a strong activation of L-type calcium channels [Adermark and Lovinger (2007), their Fig. 1A (http://www.jneurosci.org/cgi/content/full/27/25/6781/F1)]. Specifically, coincident depolarization of the postsynaptic cell to −50 mV and paired-pulse afferent stimulation in the presence of the L-type calcium channel activator 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methylester (FPL64176) induced a dose-dependent decrease in EPSC amplitude recorded from striatal medium spiny neurons (FPL-LTD) [Adermark and Lovinger (2007), their Fig. 1B (http://www.jneurosci.org/cgi/content/full/27/25/6781/F1)]. FPL also produced a gradual increase in the paired-pulse ratio, suggesting that synaptic depression was attributable to a reduction in presynaptic release of neurotransmitter [Adermark and Lovinger (2007), their Fig. 1E (http://www.jneurosci.org/cgi/content/full/27/25/6781/F1)].
To get to the molecular mechanisms, the authors examined whether the processes involved in HFS-LTD also play a role in FPL-LTD. Like HFS-LTD, FPL-LTD required postsynaptic depolarization, increased intracellular calcium, and activated L-type calcium channels because hyperpolarization, intracellular perfusion of BAPTA, and blockade of L-type calcium channels blocked FLP-LTD [Adermark and Lovinger (2007), their Fig. 2 (http://www.jneurosci.org/cgi/content/full/27/25/6781/F2)]. Furthermore, blockade of CB1 receptors blocked induction of FLP-LTD [Adermark and Lovinger (2007), their Fig. 3 (http://www.jneurosci.org/cgi/content/full/27/25/6781/F3)]. Finally, FLP-LTD could not be induced in the absence of presynaptic stimulation [Adermark and Lovinger (2007), their Fig. 5 (http://www.jneurosci.org/cgi/content/full/27/25/6781/F5)].
Despite the shared characteristics between HFS-LTD and FPL-LTD, FPL-LTD has a number of interesting differences. Metabotropic glutamate receptor (mGluR) activation has been implicated in corticostriatal LTD because of the positive coupling to the phospholipase C (PLC) pathway and release of intracellular stores of calcium. However, blockade of mGluR1 receptors failed to block FPL-LTD, suggesting that strong activation of L-type calcium channels can override the requirement for PLC-dependent calcium release. The PLC blocker U73122 [1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H- pyrrole-2,5-dione] also did not block FPL-LTD [Adermark and Lovinger (2007), their Fig. 4A,B (http://www.jneurosci.org/cgi/content/full/27/25/6781/F4)]. Blockade or genetic deletion of dopamine D2 receptors causes loss of HFS-LTD (Reynolds and Wickens, 2002). Surprisingly, FPL-LTD was not blocked by the D2 receptor antagonist** sulpride [Adermark and Lovinger (2007), their Fig. 4C (http://www.jneurosci.org/cgi/content/full/27/25/6781/F4)]. These data collectively suggest that activation of L-type calcium channels may be the final common pathway for LTD induction. Moreover, FPL-LTD occluded subsequent induction of LTD by high-frequency stimulation of cortical afferents [Adermark and Lovinger (2007), their Fig. 4F (http://www.jneurosci.org/cgi/content/full/27/25/6781/F4)], indicating that FPL-LTD and HFS-LTD are mediated by the same pathway.
It is interesting that FLP-LTD is D2 dopamine receptor independent. Dopamine-dependent changes in synaptic efficacy of corticostriatal terminals has been shown by many groups. In rodent models of Parkinson's disease, such as reserpine treatment or lesion with 6-hydroxydopamine, there is a complete loss of HFS-LTD (Kreitzer and Malenka, 2007). It will be very interesting to see whether FLP-LTD can be induced in dopamine-depleted rodents. Although this study has shown that FPL-LTD is independent of D2 receptor activation, a D1-type receptor-mediated pathway also has been implicated in HFS-LTD (Centonze et al., 2003). In addition, pharmacological rescue of corticostriatal LTD in mouse models of Parkinson's disease with CB1 and D2 receptor agonists can rescue the motor impairments associated with dopamine depletion (Kreitzer and Malenka, 2007). The next important experiment will be to test the therapeutic potential of FPL64176 by examining whether FPL-LTD is intact in dopamine-depleted animals, and if so, whether FPL64176 can rescue motor deficits in animal models of Parkinson's disease.
Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.
- Correspondence should be addressed to Mazen A. Kheirbek at the above address.