Cyclic AMP and Afferent Activity Govern Bidirectional Synaptic Plasticity in Striatopallidal Neurons

Abstract

Recent experimental evidence suggests that the low dopamine conditions in Parkinson's disease (PD) cause motor impairment through aberrant motor learning. Those data, along with computational models, suggest that this aberrant learning results from maladaptive corticostriatal plasticity and learned motor inhibition. Dopaminergic modulation of both corticostriatal long-term depression (LTD) and long-term potentiation (LTP) is proposed to be critical for these processes; however, the regulatory mechanisms underlying bidirectional corticostriatal plasticity are not fully understood. Previously, we demonstrated a key role for cAMP signaling in corticostriatal LTD. In this study, mouse brain slices were used to perform a parametric experiment that tested the impact of varying both intracellular cAMP levels and the strength of excitatory inputs on corticostriatal plasticity. Using slice electrophysiology in the dorsolateral striatum, we demonstrate that both LTP and LTD can be sequentially induced in the same D2-expressing neuron and that LTP was strongest with high intracellular cAMP and LFS, whereas LTD required low intracellular cAMP and high-frequency stimulation. Our results provide a molecular and cellular basis for regulating bidirectional corticostriatal synaptic plasticity and may help to identify novel therapeutic targets for blocking or reversing the aberrant synaptic plasticity that likely contributes to motor deficits in PD.

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

“…D2R agonist activation, presumably by activating Chl D2Rs, restored LTD in iMSNs in the iMSN-Drd2KO mice. Our data suggest that D2R-cAMP signaling has a modulatory role in the in-duction of iMSN LTD, which is consistent with previous findings (Augustin et al, 2014; Kreitzer and Malenka, 2005). We have confirmed and extended previous findings on the role of D2Rs in striatal LTD by identifying two distinct cellular pathways for the modulation of LTD induction, both of which require the activation of D2 and CB 1 receptors.…”

“…Bath application of sulpiride (5 mM) also blocked LTD in control slices (Figure 5F; 102% ± 6%, p > 0.05). D2R activation paired with the HFS protocol enhances LTD (Augustin et al, 2014). If LTD induction is mediated by D2Rs located on iMSNs, then the addition of quinpirole (5 µM), a D2R agonist, should restore HFS LTD in the Chl-Drd2KO mice.…”

“…As a result, we decided to use a conventional stimulation protocol, HFS, which has been used by many laboratories and reliably induces D2R-dependent LTD (Augustin et al, 2014; Calabresi et al, 1994; Choi and Lovinger, 1997; Kreitzer and Malenka, 2005; Lerner and Kreitzer, 2012; Wang et al, 2006). No LTD induction protocol in brain slices can replicate precisely what occurs in vivo , and thus the purpose of brain slice experiments is to determine whether and when particular mechanisms contribute to plasticity.…”

“…These two receptors are expressed on iMSNs and are oppositely coupled to cyclic AMP (cAMP) production, which affects LTD induction (Shen et al, 2008). Low levels of intracellular cAMP are permissive for LTD induction, whereas high levels inhibit LTD induction (Augustin et al, 2014). The activation of A2A receptors leads to increased cAMP signaling and protein kinase A (PKA) activation, which then inhibits mGluR5 signaling via the regulator of G protein signaling type 4 (RGS4), preventing the mobilization of eCB and ultimately inhibiting LTD.…”

Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons

“…1) (Fink et al, 1992;Ferré et al, 1993;Hersch et al, 1994Hersch et al, , 1995Ince et al, 1997). These receptors show functional interaction and regulate the AC5/cAMP/PKA signaling, which in turn is important for the long-term potentiation of the corticostriatal synapses and motor learning (Brandon et al, 1998;Price et al, 1999;Svenningsson et al, 2000;Onali and Olianas, 2002;Augustin et al, 2014). In this study, we explored interactions between the aforementioned transient neuromodulatory signals via G olf -and G i/o -coupled receptors in MSNs and how they affect the downstream cAMP/PKA signaling using quantitative kinetic modeling.…”