Coordinated Regulation of Synaptic Plasticity at Striatopallidal and Striatonigral Neurons Orchestrates Motor Control

Abstract

The basal ganglia play a critical role in shaping motor behavior. For this function, the activity of medium spiny neurons (MSNs) of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson's disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD) by inhibiting small-conductance Ca(2+)-activated K(+) channels (SKs) of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB)-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling in vivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control.

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

“…It has been speculated that eCB LTD can be induced more reliably at iMSN synapses than dMSN synapses (Kreitzer and Malenka, 2007), and this may depend on induction conditions (Shen et al, 2008; Trusel et al, 2015). This topic has remained controversial despite several reports of LTD occurring in both MSN subtypes (Bagetta et al, 2011; Picconi et al, 2011; Shen et al, 2008; Wang et al, 2006, 2017; Wu et al, 2015).…”

“…Given that this signaling is restricted to iMSNs, the involvement of iMSN D2Rs in LTD will be restricted to this MSN subtype. A few reports have suggested that this is the case (Kreitzer and Mal-enka, 2005; Shen et al, 2008; Trusel et al, 2015). However, eCB-LTD at synapses onto dMSNs has been observed (Bagetta et al, 2011; Picconi et al, 2011; Shen et al, 2008; Wang et al, 2006, 2017; Wu et al, 2015) and is prevented by the D2R antagonist in these neurons (Bagetta et al, 2011; Wang et al, 2006).…”

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

“…Although these striatal synaptic defects have been proposed to be the cause of repetitive and compulsive grooming behavior in Shank3B mutant mice, direct evidence to support this hypothe- act as retrograde signaling to activate presynaptically located CB1 receptors (CB1Rs) to reduce neurotransmission. However, there is controversy in the literature as to whether the eCB-LTD can be induced at glutamatergic synapses onto both D1 and D2 MSNs because high-frequency electrical stimulation (eHFS) might recruit intrastriatal dopaminergic and cholinergic signaling that can modulate this form of LTD (56)(57)(58)(59)(60). We thus started out to test whether the induction protocol, pairing HFS (4 trains of 100 Hz/s given at 10-second interval) of presynaptic glutamatergic afferent fibers by placing a stimulating electrode at the inner edge of the corpus callosum (instead of intrastriatal stimulation) and postsynaptic depolarization (DP) of MSNs (HFS/DP), was able to induce LTD in both types of MSNs and whether LTD could be blocked by a CB1R antagonist in both types of neurons.…”

Striatal synapses, circuits, and Parkinson's disease

“…By contrast, chemogenetic activation of G s signaling in dSPNs (mimicking ON-state signaling) aggravated dyskinesia [41]. Several other strategies of normalizing aberrant plasticity also improved behavior, further implicating striatal synaptic plasticity in the disease mechanisms [42,43]. …”