Started on one of those exercises, paraphrasing/comments on the paper. (Didn't finish up but thought I would start posting something before I forgot. For some reason my DOI links started messing up and I forgot spaces issues.)
General paper (Corkrum et al., 2020) http://doi.org/10.1016/j.neuron.2019.12.026
ABBREV
A1 Adenosine type 1
AST Astrocytes
Ca Calcium
DA Dopamine
NAc Nucleus Accumbens
...
ABSTRACT
Synaptic released DA
---Astrocytes in NAc respond w/ ^Ca2+ Signaling
---ATP/adenosine release stimulated
---Excitatory synaptic transmission depressed by activation of presynaptic A1R
Amphetamine enhances processes
---Stimulation of astrocytes
Astrocytes moderate behavioral effects of amphetamine
RES
Methods and markers…tbd
---Optogenetic technique, GCaMP6f s (Ca2+ indicator) but also GCaMP3?
---Local dopamine application
---Ca2+ cocktail
-----(TTX, CNQX, AP5, MPEP, LY367385, picrotoxin, CGP5462, atropine, CPT, suramin)
Abolition of astrocytic Ca2+ responses to DA effects by some drugs
---Flupenthixol – Relatively nonselective antipsychotic
---D1 antagonist SCH 23390
---
But not D2 antagonist sulpiride
---Nor ‘Cocktail’
[~Astrocytes respond to DA through D1-receptor type signaling]
DA-excitatory synaptic regulation mediated by astrocytes
---Measurement of excitatory postsynaptic currents in MSNs (medium spiny neurons)
---Local and synaptically released DA ^AST Ca2+, depressed EPSC
---Enhancement of paired pulse ratio (PPR) suggested presynaptic mechanism
--- IP3R2(-/-) mice – Astrocyte Ca2+ levels unaffected by DA
---Selective g-protein signaling ablation (GDPβS) also led to DA not affecting Astrocyte Ca2+ levels
D1-like receptor astrocytic specificity
---Selective deletion D1 receptor gene (DRD1 flox/flox w/ AAV8-GFAP-mCherry-Cre) in NAc
--- SKF 38393 as test of neuronal sensitivity to D1 signaling in GFAP-D1-/-
------Response to ATP but not DA in GFAP-D1-/- [Ca2+ mechanisms present]
---?tonic D1 receptor activation of basal AST Ca2+ signaling
Adenosine
---Da-evoked synaptic depression prevented by A1 receptor antagonist CPT
------ Cyclopentyltheophylline (‘relatively selective’ for A1)
---Exogenous application of adenosine let to similar depression as DA
--- ***Even in GDPβS and IP3R2(-/-) conditions
[~adenosine downstream astrocytic Ca2+ signalling]
DREADDs
---designer receptors exclusively activated by designer drugs (DREADDs)
------Is GProtein astrocytic signaling enough?
---Clozapine-N-oxide to activate Gq-DREADD
------Induced AST Ca2+ elevation, ^PPR sugg of presynaptic mech
------DREADD-Med syn reg prevented by CPT while ^Ca2+ not affected
Amphetamine
---AMP ^Ca2+ osc freq --> depressed EPSCs
------Blocked by flupenthixol
---In GDPβS astrocytes, and IP3R2(-/-) and GFAP-D1(-/-) slices
------AMP Astrocytic ^Ca2+ absent, depressed EPSCs
not present
---AMP synaptic depression abolished by CPT (w/o affecting AST ^Ca2+)
AMP.2 – behavior
---Amphetamine locomotion enhancement reduced in IP3R2(-/-) and GFAP-D1(-/-) mice
DISC
Astrocytes in this study from NAc core
Results= D1 activation, --- ?D5 partial
------(What’s the deal with D2-like receptors and amisulpiride?)
------Is it brain region specific? (D1/D2 balance? Coreceptors?)
Compare --- Ca2+ increases in the hippocampus and globus pallidus (Cui et al., 2016; Jennings et al., 2017),
Contrast - (D’Ascenzo et al., 2007) failed to detect Ca2+ changes i.r.t. SKF 38393 in NAc
---SKF-38393 was used in this study (Corkrum) to indicate neuronal sensitivity to D1 in D1(-/-)
------(?D1/D5 partial agonism. What are associated mechanisms? Biased ligand?)
---D2 led to basal Ca2+ levels in AST in hippocampus, GP (Cui et al., 2016; Jennings et al., 2017),
IP3 signaling major player for Ca2+ in astrocytes
---D1/PLC activation/IP3
------rather than D1-like/Gs/cAMP (?independent cAMP levels)
[Exogenous application of DA more effective than synaptic release of DA (63v35 %]
------?experimental limitations, subpopulations (NAc core), opto-stim lim
DA depresses excitatory transmission
---Contrast – direct activation of D1 in excitatory presynaptic terminals
---This - ATP/adenosine intermediate
Corkman discussion
quote
“ (1) astrocytes express D1R;
(2) astrocytes respond in vivo and in slices to synaptically released dopamine with Ca2+ elevations mediated by activation of D1Rs;
(3) dopamine-evoked synaptic depression was absent when astrocyte activation was blocked by GDPβS loading and in IP3R2(-/-) mice;
(4) dopamine-evoked synaptic depression was absent in the GFAP-D1(-/-) mice that lacked D1
receptors specifically in astrocytes. “
~[5] Selective activation of DREADD-exp astrocytes depresses synaptic transmission through A1R-mediated mechanism
Proposal
“ Synaptically released dopamine activates D1 receptors in astrocytes, increasing their intra- cellular Ca2+ and stimulating the release of ATP/adenosine, which acts on presynaptic A1 receptors to depress excitatory synaptic transmission"
An addition to other synaptic mechanisms for DA
---Reg of presynaptic conductance
---Mod post-synaptic firing
---NMDA-dep LT synaptic depression
---(This study)
Comp: NAc Astrocytes prop to regulate neuronal excitability/addiction through
---Release of glutamate i.r.t .mGluR5 stimulation (or DREADDs activation)
Hippocampal astrocyte ?Release of distinct gliotransmitters in response to different stimuli
------https://elifesciences.org/articles/32237 (by authors in eLife…)
------Adenosine/glutamate interaction
Astrocytes in addiction
---Extracellular/released glutamate (Scofield et al., 2015) and some mechanism w/ mGlu type II?
---Astrocytes partially responsible for synaptic effects of cocaine
Questions and various thoughts
How is this supposed adenosine (v.ATP?) effector released (from astrocytes?) to lead to ESTdepression?
------(P2x7?, selective exocytosis, connexin v. pannexins?vs… doi:10.1038/cdd.2009.131, Sxc-)
------^Ca2+ as agent driving Adenosine ?ATP release and synaptic regulation
---Timeframe and speed of release after Ca2+ (Swapna, Bondy and Morikawa, 2016)
---[Adenosine is accumulated in astrocytes by various means
------Concentrative and equilibrative nucleoside transporters CNT2,3 ENT-1-4
--- [Adenosine (P) by Adenosine Kinase to AMP, or deaminated to inosine adenosine deaminase]
[?testing – dnSNARE conditional expression to limit vesicular release ATP?]
[Adenosine A1 / sleep connection ]
[Adenosine A1 / eating ? connection behind AMP anorexigenic effects (Yang, Qi and Yang, 2015) ]
(Is Cyclopentyltheophylline really that selective for A1 at the doses used? (Also stimulant effects A2 vs. A1, PDE activity?) )
---?Use of NAc core subpopulation as reason behind D1 selectivity (vs. D2 in NAc shell)
------( Adenosinergic heteromers (A1/D1, A2A/D2))
Glutamate / NMDA (+AMPA) not reviewed thoroughly even though main reference of synaptic depression includes (Wang et al., 2012)
---?Astrocytic dysregulation over time
------EAAT2 (&EAAT1) Glutamate uptake
------Sxc- Glutamate release (in extrasynaptic regions?)
(Do astroglia have relevant amounts of NET, ~DAT transporters?)
What about TAAR?
---TAAR1 overexpression decreased astrocyte glutamate clearance Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes (Cisneros and Ghorpade, 2014)
---Interestingly, SCH23390 the D1 receptor antagonist also opposed effects of another TAAR agonist (RO5263397) (Espinoza et al., 2018)
Astrocytes (hippocampal) express CB1Rs. CB1R-induced Ca2+ elevations.
---Might CB1 modulation contribute to dysregulation or protection (say minocycline vs. THC vs. rimonabant)??
---mGlur1 mediated Endocannabinoid synaptic potentiation
------ (Navarrete and Araque, 2010)
Lithium interactions with IP3R [on the endoplasmic reticulum / sarcoplasmic reticulum
---? Downregulation to oppose possible upregulation by meth/amp
---D1 receptor stimulation (selective or meth) increases RyR-1, 2 receptors
------ (Kurokawa et al., 2011)
Drugs & Mechanisms to review in context
---Riluzole - ? Upregulate EAAT2 and glutamate clearance
---Mglur antagonism
------LY367385 (?in Ca2+ assay) or other mglur1 antagonists
---Fasoracetam nonselective mglur antagonist
---Minocycline
---Memantine – NMDA, Sxc
---N-acetyl cysteine
------What about random adenosine analogs (cordyceps/cordycepin?)
---AMPA antagonism (NBQX)
Overall
Combination PFC Glutamate + VTA DA signals converging on NAcCore MSNs
------with selective astroglia local modulation
D1 'Direct' striato-nigral pathway for distinct movements (locomotion), behaviors
D2 ‘Indirect’ striato-pallidal – discounting alternative actions
References
Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity
(Corkrum et al., 2020)
http://doi.org/10.1016/j.neuron.2019.12.026
Differential Dopamine Regulation of Ca 2+ Signaling and Its Timing Dependence in the Nucleus Accumbens
(Swapna, Bondy and Morikawa, 2016)
http://doi.org/10.1016/j.celrep.2016.03.055
Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core
(Wang et al., 2012)
http://doi.org/10.1113/jphysiol.2012.235200
Neuronal activity determines distinct gliotransmitter release from a single astrocyte
(Covelo and Araque, 2018 )
https://elifesciences.org/articles/32237
Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking
(Scofield et al., 2015)
http://doi.org/10.1016/j.biopsych.2015.02.016
Reviews & Major
Astrocytes
Human astrocytes: structure and functions in the healthy brain
(Vasile, Dossi and Rouach, 2017)
http://doi.org/10.1007/s00429-017-1383-5
Astrocytes: Role and Functions in Brain Pathologies
(Siracusa, Fusco and Cuzzocrea, 2019)
http://doi.org/10.3389/fphar.2019.01114
Physiology of Astroglia
(Verkhratsky and Nedergaard, 2017)
http://doi.org/10.1152/physrev.00042.2016
Gliotransmitters travel in time and space
(Araque et al., 2014)
http://doi.org/10.1016/j.neuron.2014.02.007
Astrocytes Control Food Intake by Inhibiting AGRP Neuron Activity via Adenosine A1 Receptors
(Yang, Qi and Yang, 2015)
http://doi.org/10.1016/j.celrep.2015.04.002
Ca2+-Dependent and Ca2+-Independent ATP Release in Astrocytes
(Xiong et al., 2018 )
http://doi.org/10.3389/fnmol.2018.00224
TAAR
The case for TAAR1 as a modulator of central nervous system function
(Rutigliano, Accorroni and Zucchi, 2018)
http://doi.org/10.3389/fphar.2017.00987
Biochemical and functional characterization of the trace amine-associated receptor 1 (TAAR1) agonist RO5263397
(Espinoza et al., 2018)
http://doi.org/10.3389/fphar.2018.00645
Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes
(Cisneros and Ghorpade, 2014)
http://doi.org/10.1016/j.neuropharm.2014.06.011
IP3R
IP3 accumulation and/or inositol depletion: Two downstream lithium's effects that may mediate its behavioral and cellular changes
(Sade et al., 2016)
http://doi.org/10.1038/tp.2016.217
Ryanodine
Dopamine D1 receptor signaling system regulates ryanodine receptor expression after intermittent exposure to methamphetamine in primary cultures of midbrain and cerebral cortical neurons
(Kurokawa et al., 2011)
http://doi.org/10.1111/j.1471-4159.2011.07366.x
Adenosine
The Role of Adenosine Receptors in Psychostimulant Addiction
(Ballesteros-Yáñez et al., 2018)
http://doi.org/10.3389/fphar.2017.00985
Adenosine signaling and function in glial cells
(Boison, Chen and Fredholm, 2010)
http://doi.org/10.1038/cdd.2009.131
(Effect of adenosine kinase, adenosine deaminase and transport inhibitors on striatal dopamine and stereotypy after methamphetamine administration)
(Gołembiowska and Żylewska, 2000)
http://doi.org/10.1016/S0028-3908(00)00024-1
System xc-
The cystine/glutamate antiporter system xc- in health and disease: From molecular mechanisms to novel therapeutic opportunities
(Lewerenz et al., 2013)
http://doi.org/10.1089/ars.2011.4391
Cannabinoids
Endocannabinoids Potentiate Synaptic Transmission through Stimulation of Astrocytes
(Navarrete and Araque, 2010)
http://dx.doi.org/10.1016/j.neuron.2010.08.043
www.ncbi.nlm.nih.gov
www.nature.com
www.nature.com