Developmental alterations of DHPG-induced long-term depression of corticostriatal synaptic transmission: switch from NMDA receptor-dependent towards CB1 receptor-dependent plasticity

Abstract

In animal models of early Parkinson's disease (PD), motor deficits are accompanied by excessive striatal glutamate release. Blockade of group I metabotropic glutamate receptors (mGluRs), endocannabinoid degradation and nitric oxide (NO) synthesis combats PD symptoms. Activation of group I mGluRs with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) induces long-term depression of corticostriatal transmission (LTD(DHPG)) in the adult mouse striatum requiring NO synthesis downstream to cannabinoid CB1 receptor (CB1R) activation suggesting a dual role for LTD(DHPG): neuroprotective by down-regulation of glutamatergic transmission and, under certain circumstances, neurotoxic by release of NO. We report now that LTD(DHPG) undergoes a developmental switch from N-methyl-D-aspartate (NMDA)-receptor-dependent/CB1R-independent to NMDA receptor-independent/CB1R-dependent plasticity with NO playing an essential role for LTD(DHPG) at all developmental stages. The gain in function of CB1R is explained by their developmental up-regulation evaluated with real-time reverse transcription-polymerase chain reaction. These findings are relevant for the pathophysiology and therapy of PD as they link the activation of group I mGluRs, endocannabinoid release, and striatal NO production.

Long-Lasting Impairment of mGluR5-Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration

“…Metabotropic GluR 1/5 are central in the modulation of striatal plasticity, which involves both these receptor subtypes, mutually with dopamine and endocannabinoid CB1 receptors (Sung et al, 2001; Mao et al, 2005; Chepkova et al, 2009). Repeated involuntary administration of cocaine leads to a progressive inhibition of DHPG-induced mGluR 1/5 activation and LTD in the core nucleus accumbens, lasting up to 28 days after cocaine administration (Huang et al, 2011), whereas 3 weeks of cocaine abstinence after short-term self-administration abolishes striatal LTD expression (Knackstedt et al, 2014).…”

The GABAAreceptor agonist muscimol induces an age- and region-dependent form of long-term depression in the mouse striatum

“…In the DLS, synaptic depression induced by muscimol is not mimicked by WIN 55,212-2 at a concentration that induces LTD in the NAc of adolescent mice. The ability of this cannabinoid receptor agonist to induce LTD in the DLS is likely influenced by the experimental conditions, as described in previous studies (Huang et al 2001;Kreitzer and Malenka 2005;Sergeeva et al 2007;Chepkova et al 2009;Clarke and Adermark 2010;Zhang et al 2015).…”

Presynaptic long-term depression mediated by Gi/o-coupled receptors

“…Nitric oxide (NO) signaling can intersect with GPCR-mediated LTD through NO-signaling pathway-mediated Ca 2+ release from presynaptic internal stores and subsequent activation of Ca 2+ -sensitive LTD mediators. Protein kinase G (PKG)-mediatedphosphorylation of release machinery may also contribute to these forms of LTD [40–42]. While these mechanisms can be recruited for presynaptic LTD induction, the maintenance of this form of LTD requires long-lasting changes at axon terminals possibly accomplished by alterations in protein translation or posttranslational modification.…”

“…Moreover, activation of GIRKs produces STD that can prevent the induction of CB1R-dependent LTD at some synapses [27] and may play a role in CB1R-dependent LTD induction at others [72]. In addition to presynaptic VDCC and potassium channels, some evidence exists to support a role for presynaptic NMDARs as downstream targets of CB1R activation [37, 74], as well as NO at striatal synapses [40, 75, 76]. …”