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When it comes to Parkinson's disease (PD), the first impression that comes to most people's minds is trembling limbs and stiff
postures.
This is all because of damage to the striatum and decreased dopamine (DA) secretion, resulting in impaired
motor function.
In the striatum, the role played by the dorsolateral striatum (DLS) is particularly important
.
In DLS, about 95% of neurons are spiny projection neurons (SPNs).
SPN can be divided into direct path dSPN and indirect path iSPN
according to its projection properties.
The balance of dSPN/iSPN is essential
for motor function.
When dSPN/iSPN dysfunction, movement disorders occur, one of which is Parkinson's disease
.
Previous studies have found that when the body is moving, the striatum releases DA to act on the Gs coupled to D1 receptor on the surface of dSPN, increasing the concentration of intracellular cAMP and activating protein kinase A (PKA); On the other hand, DA also acts on the Gi/o coupling D2 receptor on the surface of iSPN, thereby inhibiting PKA
.
In addition to DA, other neuromodulators such as adenosine may also be involved in motor regulation, and studies have found that Gs coupled adenosine A2A receptor is specifically expressed in iSPN, and activation of this receptor will activate PKA in iSPN and enhance excitatory synaptic transmission.
However, Gi-coupled adenosine A1 receptors are specifically expressed in dSPN and multiple input presynaptic terminals, and knocking out adenosine receptors affects motor function
.
However, the precise dynamics of PKA in DLS during exercise remains to be determined and whether other neuromodulators such as adenosine are involved in this process and need to be further explored
.
Recently, Nature magazine published the research results of Haining Zhong's research group at Oregon Health and Science University (OHSU): "Locomotion activates PKA through dopamine and adenosine in striatal neurons.
"
。 They achieved in vivo PKA imaging of DLS SPN, discovering for the first time how neuromodulators regulate PKA signaling
within iSPN during exercise.
Unambiguously revealed that adenosine is a neurotransmitter that works in opposition to dopamine, suggesting new avenues
for drug development.
10.
1038/s41586-022-05407-4
of PKA by DA The author injected adeno-associated virus (AAV) (a PKA probe) into DLS in D1R-Cre or Adora2a-cre mice, implanted GRIN lens, and added two-photon fluorescence lifetime microscopy (2pFLIM) technology to achieve in vivo imaging of dSPN or iSPN PKA for the first time , PKA activity
in SPN under basal conditions was successfully discovered.
After the high expression of PKA in SPN is clarified, the next step is to analyze how DA regulates PKA activity in SPN (polysecretion tonic DA under basal conditions in mice, special conditions such as polysecretion of phasic DA during exercise).
The authors injected mice
intraperitoneally with the D1R antagonist SKF 83566 (SKF) or the D2R antagonist etipride (Etic) at different times.
Finally, tonic DA increased PKA activity in dSPN and weakened PKA activity in iSPN, while phasic DA significantly increased PKA activity in dSPN but did not weaken PKA activity
in iSPN.
In summary, PKA activity in DLS dSPN and iSPN was regulated
differently between tonic and phasic DA.
10.
1038/s41586-022-05407-4
Motion activates PKA of dSPN and iSPN
To further explore the relationship between motion and PKA activity within two types of SPNs, the authors combine the 2pFLIM and treadmill locomotion
paradigms.
First, to test whether animal movement was affected by PKA activity manipulation, mice were given two different classes of PKA activity antagonists, Rp-8-Br-cAMPPs or H89, and found that the mice reduced exercise levels by 80%, suggesting that PKA activity of DLS affects exercise
.
The authors then specifically expressed PKl (a PKA-suppressing protein; The full expression of PKl by DLS was ensured by 8 injection sites), and the exercise level of mice was significantly reduced, suggesting that PKA in iSPN and dSPN was necessary
for normal exercise.
After clarifying the importance of PKA for exercise, the authors explored how PKA levels within SPN cells are affected
by exercise.
They found that the activity level of dSPN and iSPN PKA increased significantly during exercise, and the iSPN increased more; And with the extension of the exercise duration, the activity of dSPN and iSPN PKA increased significantly
.
In summary, exercise requires striatal PKA function and is closely related
to the PKA level of the two types of SPN.
10.
1038/s41586-022-05407-4III
.
Adenosine A2A receptor mediates iSPN PKA activation
To explore which neurotransmitters other than DA are involved in the activation
of iSPN PKA.
The authors introduce the forced motion paradigm, which can also activate PKA of two types of SPNs, with iSPN PKA having a higher
activation amplitude.
The authors found that intraperitoneal injection of SKF in forced exercise mode significantly reduced the exercise-induced PKA response in dSPN, confirming that this PKA activity is dependent on DA; Intraperitoneal injection of Etic enhances the activation of iSPN PKA, suggesting that the activation of iSPN PKA is not caused by DA
.
At the beginning of the paper, it is pointed out that Gs coupled adenosine A2A receptor is selectively expressed in iSPN, so it is reasonable to speculate that motor activation of iSPN may be mediated
by A2A receptor.
To test this hypothesis, the authors administered an A2A receptor antagonist in mouse DLS and found that basal PKA activity in iSPNs, as well as exercise-induced PKA activity, was reduced
.
The A1 receptor antagonist DPCPX was given in mouse DLS and found to slightly reduce iSPN basal PKA activity without affecting exercise-activated iSPN PKA levels
.
The above results suggest that the activation of iSPN PKA is mediated by adenosine A2A
receptors.
10.
1038/s41586-022-05407-4
Exercise increases DLS adenosine levels
So, according to the research routine, After clarifying the level of iSPN PKA under adenosine activation and under exercise, how is the release level of DLS adenosine affected by exercise?
The authors introduce the adenosine sensor GRABAdo1.
0
.
The authors made mice express GRABAdo1.
0 by AAV injection within DLS neurons, recording adenosine release levels
through fiber photometry.
Finally, it was found that the level of adenosine in DLS increased significantly when the mice exercised.
It accumulates with the duration of exercise, suggesting that exercise increases the level of
DLS adenosine.
The extracellular transformation of ATP is thought to be the main mechanism of adenosine production, and CD73 is an essential nucleotidase
for this transformation.
To explore the upstream mechanism of adenosine increase, the authors administered APCP within mouse DLS to antagonize CD73 and inhibit the conversion of extracellular ATP to adenosine
.
Finally, it was found that the iSPN PKA activated by exercise was significantly reduced and dSPN PKA was significantly increased, but it had no effect on iSPN PKA under basal conditions, and dSPN PKA
was slightly reduced.
In addition, the authors found that administration of APCP significantly reduced the adenosine release process
under exercise conditions.
These results suggest that exercise-induced DLS adenosine accumulation is associated
with extracellular ATP metabolism.
Later, the authors also explored how adenosine activation of iSPN PKA affects movement
.
The authors applied adenosine and dopamine receptor antagonists at the same time, and found that the exercise ability of mice remained at the background level, indicating that adenosine and dopamine in DLS can affect the body's exercise level, and the two effects antagonize
each other.
Finally, the authors explore the neural mechanisms
by which adenosine and dopamine affect movement.
The authors used two-photon calcium imaging based on GRIN lens and found that motion-activated dSPN versus iSPN
.
The administration of A2A receptor antagonists to mice showed a significant decrease in iSPN calcium signaling and a slight increase in dSPN calcium signaling.
When SKF was administered, it was found that dSPN calcium signaling was significantly reduced and iSPN calcium signaling was slightly reduced; With the administration of Etic, it was found that increasing the iSPN calcium signaling did not affect the dSPN calcium signaling
.
The above results show that adenosine and dopamine affect the level of body movement by changing the SPN activity in DLS
.
10.
1038/s41586-022-05407-4SummaryThe
authors combined transgenic animals, PKA and adenosine probes and endoscopic two-photon imaging, It was confirmed that adenosine and dopamine in DLS affected exercise through SPN PKA activity, and the two were antagonistic
.
This study is the first to explore the neural mechanism of striatal adenosine affecting PKA activity and body movement, and it is of great significance to apply PKA in vivo imaging technology to basic function research!
The loss of dopamine in the striatum can lead to brain disorders such as Parkinson's disease
.
Adenosine is antagonistic to dopamine, so adenosine receptors
can be considered potential therapeutic targets.
The results of this study may help to design strategies to treat striatal dysfunctionIn the research and development
of new drugs.
Written by | Edit | CICI
References: Ma, L.
, Day-Cooney, J.
, Benavides, O.
J.
et al.
Locomotion activates PKA through dopamine and adenosine in striatal neurons.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05407-4
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