Modulation of Spatiotemporal Dynamics of Striatal Direct Pathway Neurons and Motor Output by Metabotropic Glutamate Receptor 5

Core Concepts

Modulation of metabotropic glutamate receptor 5 (mGluR5) signaling bidirectionally alters the spatiotemporal coordination of striatal direct pathway neuron (dSPN) activity and correlates with changes in spontaneous motor output.

Abstract

The study investigates the role of metabotropic glutamate receptor 5 (mGluR5) in regulating the spatiotemporal dynamics of striatal direct pathway neurons (dSPNs) and their relationship to motor behavior.
Key highlights:

In vivo calcium imaging revealed that dSPNs exhibit spatially clustered co-activity patterns that vary with the animal's movement state. Co-activity is higher during rest and decreases during movement.
Pharmacological inhibition of mGluR5 using the negative allosteric modulator fenobam increased the spatially clustered co-activity of dSPNs and reduced spontaneous locomotion. In contrast, positive modulation of mGluR5 using the allosteric modulator JNJ decreased dSPN co-activity and increased locomotion.
Genetic deletion of mGluR5 specifically in dSPNs (D1 cKO mice) recapitulated the effects on spatiotemporal dSPN dynamics and reduced spontaneous motor behaviors, without altering the overall activity levels of dSPNs.
Ex vivo electrophysiology revealed that mGluR5 deletion in dSPNs increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), suggesting changes in excitatory synaptic input.
The results suggest that mGluR5-mediated modulation of excitatory synaptic strength onto dSPNs shapes their spatiotemporal coordination, which in turn correlates with changes in spontaneous motor output.

Stats

The Ca2+ event rate in dSPNs increases during movement.
Fenobam treatment reduced the mean velocity and bout length of spontaneous locomotion in mice.
JNJ treatment increased the mean velocity and decreased the time spent at rest during spontaneous locomotion in mice.
D1 cKO mice showed reduced spontaneous locomotion, digging behavior, and performance on the accelerating rotarod test.
D1 cKO mice had increased mEPSC frequency in dSPNs compared to controls.

Quotes

"Fenobam treatment uniformly reduced locomotion (Figure 2J, K), an effect that was driven more by a reduction in movement bout duration than the frequency of movement bouts (Figure 2L)."
"Systemic administration of the mGluR5 positive allosteric modulator JNJ led to decreased co-activity and increased locomotion."
"Targeted genetic deletion of mGluR5 in dSPNs (D1 cKO mice) had minimal effects on the levels of either dSPN or iSPN activity, but specifically increased the spatiotemporal coordination of dSPN activity and reduced spontaneous locomotion."

Key Insights Distilled From

Modulation of the spatiotemporal dynamics of striatal direct pathway neurons and motor output by mGluR5

by Marshall,J. ... at www.biorxiv.org 12-21-2023

https://www.biorxiv.org/content/10.1101/2023.12.20.572676v2

Deeper Inquiries

How do the changes in spatiotemporal dSPN dynamics induced by mGluR5 modulation relate to the specific kinematic features of movement, such as velocity, acceleration, and movement sequences

The changes in spatiotemporal dynamics of dSPNs induced by mGluR5 modulation are closely related to specific kinematic features of movement, such as velocity, acceleration, and movement sequences. The study demonstrated that altering mGluR5 signaling bidirectionally affected movement and spatially clustered dynamics of dSPNs without significantly changing their overall activity levels. Pharmacological inhibition of mGluR5 with fenobam increased the spatially clustered patterns of co-activity in dSPNs and reduced locomotor activity. On the other hand, positive modulation of mGluR5 with JNJ decreased the co-activity among dSPNs and increased locomotion. These changes in dSPN dynamics correlated with movement states, where co-activity was higher during rest and decreased during movement. The alterations in dSPN co-activity influenced the duration and frequency of movement bouts, reflecting changes in movement initiation, progression, and coordination. Therefore, the spatiotemporal coordination of dSPNs plays a crucial role in shaping the specific kinematic features of movement, highlighting the importance of coordinated neural activity in motor control.

What are the potential mechanisms by which mGluR5-mediated modulation of excitatory synaptic strength onto dSPNs shapes their spatiotemporal coordination, and how do these mechanisms interface with other neuromodulatory systems like dopamine

The potential mechanisms by which mGluR5-mediated modulation of excitatory synaptic strength onto dSPNs shapes their spatiotemporal coordination involve the regulation of corticostriatal synaptic plasticity. mGluR5 activation at corticostriatal synapses leads to the mobilization of endocannabinoids (eCBs), specifically 2-arachidonoylglycerol (2-AG), which modulates synaptic transmission. In vitro studies have shown that mGluR5 activation induces long-term depression (LTD) of corticostriatal synapses through eCB-dependent mechanisms. This LTD is crucial for regulating the strength of excitatory inputs onto dSPNs and influencing their collective sensitivity to convergent excitatory inputs. By modulating synaptic plasticity at corticostriatal synapses, mGluR5 signaling can constrain the spatiotemporal dynamics of dSPN activity, leading to changes in movement patterns. These mechanisms interface with other neuromodulatory systems like dopamine, which also play a role in sculpting the dynamics of SPN activity. The interaction between mGluR5-mediated synaptic plasticity and dopaminergic signaling contributes to the fine-tuning of striatal circuit function and motor control.

How might the insights from this study on the role of spatiotemporal dSPN dynamics in motor control inform our understanding of striatal circuit function in neurological and psychiatric disorders associated with movement abnormalities

The insights from this study on the role of spatiotemporal dSPN dynamics in motor control can inform our understanding of striatal circuit function in neurological and psychiatric disorders associated with movement abnormalities. Dysregulation of spatiotemporal coordination of dSPNs, as observed in the study through mGluR5 modulation, may underlie motor deficits seen in conditions like Parkinson's disease, Huntington's disease, and dystonia. For example, in Parkinson's disease, where there is a loss of dopamine signaling, alterations in the spatiotemporal dynamics of dSPNs could contribute to the characteristic motor symptoms. Understanding how changes in synaptic plasticity and neural ensemble dynamics impact motor output provides valuable insights into the pathophysiology of movement disorders. By elucidating the mechanisms that govern dSPN activity and its coordination, this research opens avenues for developing targeted interventions to modulate striatal circuit function and potentially alleviate motor dysfunction in these disorders.