Ho feto-fetoha ha lentsoe la phetoho ea glutamatergic ka Dopamine: ho tsepamisa maikutlo ho Parkinson, Huntington le mafu a Addiction (2015)

Front Cell Neurosci. 2015; 9: 25.

E hatisitsoe Inthaneteng 2015 Mar 2. doi:  10.3389 / fncel.2015.00025

PMCID: PMC4345909

Eya ho:

inahaneloang

Dopamine (DA) e bapala karolo ea mantlha mesebetsing ea makoloi le ea kelello hammoho le ts'ebetsong ea meputso ka ho hlophisa liphetho tsa glutamatergic. Haholo-holo ho striatum ho lokolloa ha DA ho potlakela ho susumetsa phetisetso ea phetisetso ea synaptic modulting ka bobeli AMPA le li-receptor tsa NMDA. Mathata a 'maloa a amanang le neurodegenerative le neuropsychiatric, ho kenyelletsa le Parkinson, Huntington le mafu a amanang le bokhoba, a bontša ho se sebetse ha lets'oao la glutamate le ho saena ha DA. Mona, re tla tsepamisa maikutlo a rona molemong oa phetisetso ea phetisetso ea phetisetso ea glutamatergic e entsoeng ke DA lipotolohong tsa mekhahlelo.

Keywords: Dopamine, receptor ea NMDA, li-receptor tsa AMPA, Tlatsetso, lefu la Parkinson, lefu la Huntington

Selelekela

Dopamine (DA) ke catecholamine e sebetsang joaloka neuromodulator ka ho bapala karolo ea bohlokoa mesebetsing ea makoloi le ea kelello hammoho le ts'ebetsong ea moputso.

Kutloisiso ea rona e kholo ea phetiso ea DA e tsoa lipatlisisong tsa sistimi ea midbrain DA e utloisisang Substantia Nigra par compacta (SNc-A9) le Ventral Tegmental Area (VTA-A10). Ea pele e qalong ea tsela e sa tsitsang eo li-neurons tsa DA li kenang tšebetsong ea methapo le ho bapala karolo ea mantlha ho laoleng mesebetsi e metle ea makoloi. Sebakeng sa li-neurons tsa DA kahare ho VTA e etsa tsela ea mesostriatal le projeke ho "ventral striatum" (kapa Nucleus accumbens, NaC) e kenyang karolo ea bohlokoa ts'ebetsong ea moputso (Paillé et al., 2010; Tritsch le Sabatini, 2012). HUena DA e bopa tšebetso ee e fapaneng kaofela bokong? Likhethong tsena ka bobeli, DA e sebetsa e le neuromodulator e laolang lipakatso tsa glutamatergic ho li-neuron tse ka sehloohong mme ka hona e laola tlhahiso ea striatal. Ho feta 95% ea li-neuron tsa striatal li emeloa ke Medium Spiny Neurons (Li-MSN; Kreitzer, 2009) sebopeho sa asymmetric se lumellana le likhakanyo tsa glutamatergic le mabitso a maiketsetso liphuthelong tsa DA. Ka hona, ts'ebetso ea li-neurons tsa DA le tokollo e hlahang ea DA kamora haufi ha sehokelo sa synaptic e susumetsa ka potlako phetiso ea synaptic, thabo e makatsang le kopanyo ea dendritic (Tritsch le Sabatini, 2012), ka mokhoa o hlalosang likarolo tse fapaneng tsa DA bokong. Haholo-holo DA e khona ho fetisa phetisetso ea glutamatergic ka phetoho ea li-converter ho li-MSNs, ka ho sebetsa ka D2-R e fumanehang ho likhakanyo tsa ts'ebetso tsa Glutamatergic kapa ka ho fetolela lipakatso tse thabisang tse kenang lipakeng tsa GABAergic le Cholinergic.

Ika thabo, mathata a 'maloa a amanang le neurodegenerative le neuropsychiatric, ho kenyelletsa le Parkinson, Huntington le mafu a amanang le bokhoba, a bonts'a ho se sebetse ha glutamate le DA ho supa ka har'a striatum. Thutong ena, re tla tsepamisa maikutlo a rona molemong oa phetisetso ea phetisetso ea glutamatergic e etsoang ke DA literekeng tse nigrostriatal le mesostriatal (Setšoantšo. (Figure11).

Setšoantšo sa 1  

Li-circuits tsa Nigrostriatal le Mesostriatal. Sagittal pono ea lipokello tse thabisang tse lipakeng tsa lipotoloho tse hulang pele le tsa mesostriatal.

Potoloho ea Nigrostriatal

DA li-neurons tsa morero oa SNc ho dorsal striatum. Sebopeho sena se na le boholo ba li-MSN tse thathamisitsoeng ka lihlopha tse peli ho latela lipalo tsa tsona tsa li-axonal le polelo ea li-receptor tsa DA.

  • DA receptor mofuta 1 (D1R) - e tsamaisa li-MSN li theha tsela e otlolohileng mme li romella li-axon tsa tsona ho GABAergic tlhahiso ea li-nuclei tsa gangal ea basal, tkarolo e ka hare ea Globus Pallidus (GPi) le Substantia Nigra pars reticulata (SNr), eo ka nako e tšoanang e romellang lipuisano tsa bona ho motor nuclei ea thalamus.
  • DA receptor mofuta 2 (D2R) - e kopantseng li-MSN li theha tsela e sa tsejoeng 'me li romella li-axon tsa tsona karolong e kantle ea Globus Pallidus (GPe), eo ka morero oa eona e hlahisang glutamatergic neurons ea Sub-Thalamic Nucleus (STN). Li-neuron tsa STN li ntan'o romella li-axon tsa tsona ho "basal ganglia tlhahiso" (GPi le SNr) moo li thehang methapo ea kutlo e ka har'a li-neurons tse hlahisang lintho.

Ts'ebetso ea tsela e otlolohileng le e sa tobang e fana ka phello e fapaneng le ea motsamao:

  1. ts'ebetso ea tsela e otlolohileng e senola lits'oants'o tsa thalamocortical mme e lebisa ho ts'ebetsong ea li-circuits tsa pele tsa cortical tse thusang ho tsamaisa.
  2. Ts'ebetso ea tsela e sa tobang ho fapana le hoo e thibela li-neurons tsa "thalamocortical" tse fokotsang drive ea pele le tsamaiso e thibelang (Kreitzer le Malenka, 2008).
  • Ho khahlisang mokhoa ona o sa tsoa qholotsoa 'me ho hlahisitsoe tlhahiso ea hore litsela tse peli li hokahane ka tsela e hlophisehileng (Dunah le Standaert, 2001; Calabresi et al., 2014).

Ka ho sebetsa ho D1R kapa D2R, DA ka tsela e fapaneng e hlophisa ts'ebetso ea tsela e tobileng le e sa tobang ka bobeli e laolang thabo ea li-MSNs ho striatum le ho tsamaisa polasetiki ea synaptic litsing tse fapaneng tsa glutamatergic. Boholo ba liphatlalatso tsa glutamatergic tse kenang dorsal striatum li tsoa cortex le thalamus. Le ha lipuisano tsa corticostriatal li ka tsamaisa leseli la koloi le tlhaiso-leseling, tse ling tsa thalamostriatal li fetisa tlhahisoleseling bakeng sa meputso ea meputso le ho falimeha (Huerta-Ocampo et al., 2014). Leha ho na le pono ena, liea-le-moea tse peli tsa corticostriatal le thalamostriatal li theha mabitso a li-synaptic le D1 le D2 MSNs le ho ba teng ha tlhahiso ea tsona ho bontša hore le bona ba kentse letsoho ts'ebetsong ea li-MSN.

Ho fumanoe liphapang tse ngata litseleng tsena. fana ka tlhahiso ea liphapang tse itšetlehileng ka tlatsetso mesebetsing ea synaptic (Smeal et al. 2008). Boithuto ba nako e tlang boa hlokahala ho etsa lipatlisiso ka karohano ea ho kenyelletsa litseleng tse otlolohileng le tse sa tobang ka kotloloho le lits'ebetso tsa ts'ebetso.

Potoloho ea Mesostriatal

Potoloho ena e simoloha ho VTA moo projeke ea DA ho fihlela D1 le D2 MSN tsa li-ventral striatum. Leha boteng ba D1 le D2 MSN ka har'a ventral striatum bo thehiloe hantle, ho na le bopaki bo bongata bo bonts'ang hore likhakanyo tse tsoang ho NAc li kanna tsa se aroloe joalo ka dorsal striatum. Ehlile ho bontšitsoe hore bobeli ba D1 le D2 MSN li kenya letsoho ho porral pallidum, athe D1 MSNs le tsona li ka etsa projeke ka kotloloho ho VTA (Lu et al., 1998; Zhou et al., 2003; Smith et al., 2013). Leha ho le phapang ena, e thehiloe hantle hore D1 le D2 MSNs ho NAc li bonts'a thepa e fapaneng ea electrophysiological (Paillé et al., 2010; Pascoli et al., 2011b, 2014b) mme o arabe ka tsela e fapaneng ho tshusumetso ya VTA (Grueter et al., 2010; Paillé et al., 2010). Ntle le karohano ena e hlakileng ea D1 le D2 e nang le MSN, ho lokela ho bua ka ho ba teng ha palo e nyane ea li-neuron tse nang le D1Rs le D2Rs (Matamales et al., 2009).

Ka mokhoa o ts'oanang ho potoloho ea nigrostriatal, DA e hlophisa le ho kenyelletsa likhakanyo tsa glutamatergic synaptic tse tsoang cortex ea pele, amygdala le hippocampus. Ho khahlisang, mefuta e fapaneng ea li-synaptic plasticity e hlalositsoe lits'ebetsong tse fapaneng tsa thabo ho D1 le D2 MSNs e fana ka maikutlo a hore mokhoa o ikhethang oa ts'ebetso ea neuronal o tsamaellanang le letšoao la DA oa hlokahala bakeng sa sephetho se tobileng se amanang le moputso (Paillé et al., 2010; Pascoli et al., 2014b).

Li-receptor tsa DA le litsela tse tšoaeang

Phetisetso ea DA e kopantsoe ke Guanine nucleotide e tlamang Protein Coupled Receptors (GPCRs). Ke li-receptor tsa metabotropic tse nang le libaka tse supileng tsa transmembrane tse kopantsoeng le liprotheine tsa G-tse lebisang ho thehoeng ha man messengersosa a bobeli le ts'ebetso kapa thibelo ea li-cascade tse latelang. Leha li-receptors tse hlano tse fapaneng tsa DA li se li bitsitsoe ho fihlela joale, hoa khonahala ho li khetholla ka lipalo tse peli tse kholo ho latela meaho ea tsona le thepa ea tsona ea meriana: (a) D1-like receptors (D1 le D5) e hlohlelletsang tlhahiso ea cAMP; le (b) li-receptor tse kang D2 tse kang D2, D3 le D4) tse fokotsang maemo a crP ea intracellular. Bokhoni ba li-receptors tsa D1-like le D2-modformers ka tsela e fapaneng e shebane le ho ts'oaroa ha cAMP, ka hona phallo ea lets'oao le tlase, ho latela ts'ebelisano ea bona le liprotheine tse ikhethang tsa G.

Li-receptor tse kang D1 ke tsona tse tsebahalang ka ho fetisisa tse hlahelang ka ho fetisisa bokong ba DA, tse fumanehang haholo kahare ho bokapele mme, ha ho bapisoa le lelapa la D2, le na le tatelano e bolokiloeng haholo (Tritsch le Sabatini, 2012). Ho tlama ha DA ka li-receptor tse kang D1 ho lebisa hoketseho ea ketsahalo ea cymbase ea adenylyl le ho phahama ha maemo a CAMP. Tsela ena e tsenya ts'ebetso ea protheine kinase A (PKA) le phosphorylation ea substrates tse fapaneng hammoho le ho kenella ha polelo ea liphatsa tsa pele tsa lefutso tse tlatsetsang karabong ea D1R ka kakaretso (Beaulieu le Gainetdinov, 2011). DARPP-32 (DA le phosphoprotein e laoloang ke cAMPk) ke e 'ngoe ea likarolo tse ithutoang haholo tsa PKA tse entsoeng ke DA ebile e fana ka mochine oa ho kenyelletsa tlhahisoleseling ho dopaminocepts neurons (Svenningsson et al., 2004). E tsamaisa taolo ea Protein Phosphatase-1 (PP-1), DARPP-32 e laola ho thaba ha methapo ea kutlo hammoho le phetisetso ea glutamatergic. Ho kenngwa tshebetsong ha tsela ea cAMP / PKA / DARPP-32 ka sebele ho eketsa ho buloa ha L-mofuta oa Ca2 + liteishene tse khothaletsang phetoho ea li-MSN ho ea boemong bo holimo ba thabo (Vergara et al., 2003). Ka nako e ts'oanang, ts'ebetso ea ts'ebetso ea tsela ena e phahamisa phosphorylation ea li-AMPAR ka bobeli le NMDAR e fana ka mochine oa taolo e tobileng ea phetisetso ea glutamatergic ka ho saena ha DA (Snyder et al., 1998, 2005).

Ho na le litla-morao tse ngata tse tsamaeang le ho etsoa ha D2R. Pele ho tsohle, li-receptor tsena li kopantsoe le liprotheine tsa Gi / o mme ts'ebetso ea tsona e fetohile hampe ho saena ha cAMP, e fokotsa phosphorylation ea liprotheine tse tlase (lipheo tsa PKA), joalo ka DARPP-32. Ka nako e ts'oanang, ts'ebetso ea D2R, ka Gβγ subunits, inhibits L-mofuta Ca2+ liteishene le ho kenya tshebetsong G-protein e kopantsoeng kahare ho Rarolla potasiamo (K+) liteishene (GIRK) tse bakang ho fokotseha hoa thabo ea methapo ea kutlo le phokotso molemongng le tokollong ea DA (Kebabian le Greengard, 1971). Ntle le moo, li-D2R li boetse li na le sephetho sa liphutheloana tse tlisang thabo e tlisoang ke ho lokolloa ha glutamate le li-Intneurons tsa ChaT ka har'a striatum moo ho kenyang letsoho ho fokotsa tokollo ea Ach (Surmeier et al., 2007).

Ho khahlisang, DA e na le tumellano e tlase ea li-D1R ha e bapisoa le D2R, e supa sephetho se fapaneng tseleng e tobileng le e sa tobang nakong ea tokollo ea tonic kapa phasic ea DA. Ho joalo, ho fanoe ka tlhahiso ea hore phasic lokolla activate D1Rs ho nolofalletsa lipallo tsa limbic ha li-activicction activatectional activate D2Rs tse kenang liphatlalatsong tsa PFC (Floresco et al., 2003; Goto le Mohau, 2005; Goto et al., 2007). Ho bohlokoa ho nahana ka litlamorao tse fapaneng tsa DA fetola mesebetsi ea libaka tsa boko tse fumanang liphetho tsa DA. Ho joalo, phetoho e fetotsoeng ea DA ea litlatsetso tse thabisang libakeng tsena e bapala karolo ea bohlokoa ho pathophysiology ea likhathatso tse ngata tsa methapo (Goto et al., 2007).

DA modulation ea li-NMDAR le li-AMPAR

DA e hlophisa ts'ebetso ea "glutamatergic synapse" ka ho sebetsa maemong a fapaneng. Pono ea khale e bontša hore DA e ka laola ts'ebetso ea li-receptor tsa ionotropic glutamate ka phokotso ea likarabo tse hlahisitsoeng ke AMPAR le keketseho ea likarabo tse hlahisitsoeng ke NMDAR (Cepeda et al., 1993; Levine et al., 1996; Cepeda le Levine, 1998; Graham et al., 2009). Haholo-holo, ts'ebetso ea D1R hangata e lebisa ho matla a maqhubu a itšetlehileng ka NMDAR, ha ts'ebetso ea D2R e baka ho fokotseha ha likarabo tse itšetlehileng ka AMPAR. Pono ena e na le bohlokoa ba bohlokoa ho striatum moo dopaminergic terminals li theha mabitso a synaptic molaleng oa li-spN tsa MSN, ha hlooho e fumana litlatsetso tse tsoang litsing tsa glutamatergic (Surmeier et al., 2007).

Ho khahlisang, li-NMDAR ka corticostriatal synapse li bonts'a likarolo tse ikhethang. Ho joalo, leha GluN2B e emetse subunit e ka sehloohong ea taolo e hlahisitsoeng sebakeng sena sa boko (Dunah le Standaert, 2001), ho bile le tlhahiso ea hore GluN2A- empa eseng GluN2B-e nang le NMDARs e baka khatello ea maikutlo ea phetisetso ea synaptic e sa kenyeng ts'ebetso ea li-neurons tsa corticostriatal empa e mpa e le li-NMDARs ho li-synapses tsa MSN (Schotanus le Chergui, 2008a). Ho khahlisang, litlaleho tsa morao-rao li bontšitse hore GluN2A le GluN2B li kenya letsoho ka mokhoa o fapaneng phapusing ea glutamatergic ho li-MSNs tsa striatal (Paoletti et al., 2008; Jocoy et al., 2011). Ha ho tlosoa hoa liphatsa tsa lefutso kapa "blockacological blockade" ea GluN2A e eketsa ts'oaetso tse tsamaeang le D1R tse tsamaeang le NMDAR, ho thibela GluN2B ho fokotsa ts'ebetso ena, ho fana ka maikutlo a khahlanong le mesebetsi ea bona. Ho feta moo, e bontšitse hore li-subunits tsa GluN2A li kenya letsoho haholo ho likarabo tsa NMDA ho D1-MSNs, athe li-subluits tsa GluN2B li nka karolo haholo likarabo tsa NMDA liseleng tsa D2R (Paoletti et al., 2008; Jocoy et al., 2011).

Boithuto bo 'maloa bo fuputse phello ea ho hlohlelletsa ha D1R ho ts'oaroa ha subunit ea NMDAR ho membrane ea synaptic. Ts'ebetso ea pharmacological ea D1R e ntlafatsa maemo a holimolimo a NMDAR (Hallett et al., 2006; Paoletti et al., 2008) le lehae la NMDAR ho kenella ka karolo ea synaptosomal membrane ka ho susumetsa ha tyrosine kinase Fyn (Dunah et al., 2004; Tang et al., 2007). Ho qaqisa haholoanyane, ho bontšitsoe hore kalafo e nang le D1R agonist (SKF38393) e lebisa ho fokotseha ho hoholo hoa li-NMDAR tsa GluN2A le keketseho e tšoanang ea bophara ba hlooho ea lesapo (Vastagh et al., 2012). Ho khahlisang ke hore kalafo e kopanetsoeng ea methapo ea corticostriatal le mohanyetsi oa GluN2A (NVP-AAM077) le agonist ea D1R e thusitse keketseho ea li-dendritic spine hlooho e bonoang ka SKF38393 feela. Ka lehlakoreng le leng, GluN2B antagonist (ifenprodil) e thibetse ts'ebetso efe kapa efe ea morphological e hlahisitsoeng ke ts'ebetso ea D1 (Vastagh et al., 2012). Leha ho le joalo, lithuto tse ling li ntse li hlokahala bakeng sa kutloisiso e phethahetseng ea karolo e ikhethang ea GluN2A- vs. Li-NMDAR tse nang le GluN2B li-moduleteng ea dendritic spine morphology ho li-stNatal MSNs.

Lithunya tsa BAC transgenic tse hlalosang EGFP ho D1R- le lisele tse nang le D2R-tse nepahetseng (Valjent et al., 2009) e sa tsoa sebelisoa ho hlahlobisisa ka hloko ho feto-fetoha ha maemo ho itšetlehileng ka DAN tsa li-MSN ka har'a litsela tse eang ka kotlolloho le tse sa tobang (Cepeda et al. 2008). Ka tumellano le lithuto tse fetileng, modX ea ho feto-fetoha ha maikutlo a thehiloeng ho D1R e ile ea lumellana le ts'ebetso ea li-neurons tsa tsela e otlolohileng. Ho fapana le hoo, D2R e fokotsang karabelo ea likarabo tse hlahisitsoeng ke glutamate e ne e ikhethile tseleng e sa tobang (André et al., 2010). Ho feta moo, lisebelisoa tsa morao-rao le tse tsoetseng pele tse kang optogenetics le Ca tse tsoetseng pele2+ imaging e bontšitse hore ts'ebetso ea li-receptors tsa D2 e fokotsa likarabo tse hlahisitsoeng ke NMDAR ka modynaptic modulation ea tokollo ea glutamate (Higley le Sabatini, 2010).

Haholo-holo liphuputso tse 'maloa tse hlalosang ho ba teng ha li-D1R le li-NMDAR libakeng tsa li-synakses tsa MSN li bonts'a ho ba teng ha tšebelisano e tobileng ea molek'hule lipakeng tsa lits'ebetso tse peli tsa li-receptor (Kung et al., 2007; Heng et al., 2009; Kruusmägi et al., 2009; Jocoy et al., 2011; Vastagh et al., 2012). Tšebelisano e tobileng pakeng tsa li-receptors tsena tse peli e ne e reriloe qalong ke Lee et al. (2002), ea bonts'itseng Co-immunoprecipitation ea D1R le GluN1 / GluN2A subunits ea NMDAR. Tšebelisano ena ha e eme, empa e fokotsehile ke ts'ebetso ea D1R (Lee et al., 2002; Lischer le Bellone, 2008). Ntle le moo, tšitiso ea tšebelisano ea D1R e nang le NMDAR e nang le li-NMDAR ka ho kena-kenana le li-peptides e lekane ho susumetsa molumo oa maqhubu a NMDAR ka hona a fana ka maikutlo a karolo e tobileng bakeng sa mokokotlo ona oa li-receptor-receptor ho phetisetso ea NMDA (Lee et al., 2002;; Brown et al., 2010). Leha ho le joalo, taba ena e rarahane ho feta hobane liseleng ka bobeli tsa "striatal neurons" le li-cell tse fetisitsoeng tsa HEK293, D1R e sebetsana ka kotloloho le GluN1 subunit ho theha mofuta o kopaneng oa oligomeric o ngoliselitsoeng ho membrane oa plasma ka boteng ba subluit ea GluN2B (Fiorentini et al. 2003). Ho feta moo, ts'ebelisano ena e hlakola ho kenella ka hare ho D1R, karabelo ea bohlokoa e lumellanang e atisang ho hlaha ka tšusumetso ea agonist (Fiorentini et al., 2003).

Liphuputso tsa morao-rao li sebelisitse mekhoa e phahameng ea ho rarolla mathata ea nanoparticle e le 'ngoe ho etsa karolo ea tšebelisano e matla lipakeng tsa D1R le NMDAR ho li-hippocampal synapses (Ladepeche et al., 2013a). Thibelo ea tšebelisano ea 'mele lipakeng tsa D1R le GluN1 ka ho kenella ha peptide e khona ho hlakola ka botlalo botsitso ba synaptic ea D1R, ka hona e fana ka tlhahiso ea hore li-D1R li bolokiloe ka mokhoa o tsitsitseng ho glutamatergic synapses ka mochine o hlokang ho sebelisana le NMDAR (Ladepeche et. 2013a). Ntle le moo, ho sitisoa ha D1R / NMDAR tataiso ho eketsa dikahare tsa NMDAR ka ho fana ka tumellano e potlakileng ea morao-rao ea li-receptors, le ho rata nako e telele ea synaptic potentiation (Ladepeche et al., 2013b). Ka ho khetheha, ts'ebetso ea D1R e fokotsa tšebelisano ea D1R / GluN1 libakeng tsa perisynaptic mme e lumella ho kenyelletsoa ha morao-rao ha li-NMDAR ka har'a denseity ea postynaptic moo ba ts'ehetsang ho kenella ha bokhoni ba nako e telele (LTP; Argilli et al., 2008; Ladepeche et al., 2013b).

Li-receptor tsa D2-mofuta oa DA le tsona li sebelisana le li-NMDAR. Boemong ba postynaptic, li-D2R li theha mofuta o itseng o rarahaneng le li-NMDAR ka C-terminal domain ea GluN2B subunit (Liu et al., 2006). Ho khahlisang, ho hlohlelletsoa ke DA ka koae (i) ho ntlafatsa tšebelisano ea D2R / GluN2B; (ii) e fokotsa botsoalle ba CaMKII le GluN2B; (iii) e theola phosphorylation e itšetlehileng ka CaMKII ea GluN2B (Ser1303); le (iv) e thibela maqhubu a li-receptor-Mediated a NMDA ho li-MSNs (Liu et al., 2006).

DA e kanna ea fetola tšebetso ea li-AMPAR tse lebisang phokotsong ea likarabo tse hlahisitsoeng ke AMPAR (Cepeda et al., 1993; Levine et al., 1996; Cepeda le Levine, 1998; Bellone le Lüscher, 2006; Engblom et al., 2008; Mameli et al., 2009;; Brown et al., 2010). Boithuto ba pele bo etsoang ho li-neurons tse nang le cultured bo bonts'itse hore ts'ebetso ea D1R ho li-stNatal MSNs e ntlafatsa phosphorylation ea AMPARs ke PKA hammoho le ts'ebetso ea amplitude ea hona joale (Price et al. 1999). Bahanyetsi ba D2R ba eketsa phosphorylation ea GluR1 ho Ser845 ntle le ho ama phosphorylation ho Ser831 (Håkansson et al., 2006). Phello e tšoanang e bonoa ho sebelisoa eticlopride, mohanyetsi ea khethiloeng oa D2R. Ho fapana le hoo, D2R agonist quinpirole e fokotsehile phosphorylation ea GluR1 ho Ser845 (Håkansson et al., 2006). Modulation ea li-receptors tsa DA e boetse e khona ho laola ho ts'oaroa ha AMPAR ho li-membrane tsa synaptic. Ka ho khetheha, kalafo e nang le agonist ea D1R e lebisa keketseho ea AMPA receptor subunits expression expression (Snyder et al., 2000; Gao et al., 2006; Vastagh et al., 2012).

DA modulation ea synaptic polasetiki

DA e bapala karolo ea bohlokoa ho fetoheng liphetoho tsa nako e telele ho matla a synaptic. E 'ngoe ea mefuta e khethiloeng ka ho fetisisa ea polasetiki ea synaptic ho striatum ke khatello ea maikutlo ea nako e telele (LTD). Ka har'a dorsal le ventral striatum mofuta ona oa polasetiki o hloka ts'ebetso e ts'oanang ea mGluR5 le liteishene tsa khalsiamo tsa voltage-gated mme e hlahisoa ke ho lokolloa ha endocannabinoids (eCBs). Li-eCB li sebetsa ka mokhoa o iketlileng ho li-receptor tsa tsona tsa CB mme li fokotsa monyetla oa ho lokolloa ha glutamate (Robbe et al., 2002; Kreitzer le Malenka, 2005).

Ho khahlisang, tmofuta oa hae oa LTD o latela ts'ebetso ea D2Rs, empa hore na ho na le khang ea hore na ho hlahisoa feela likhakanyo tsa glutamatergic ho li-MSN tsa tsela e sa tsejoeng ea dorsal striatum. Ehlile, le ha eCB-LTD e ntse e tšoauoa pele ho D2R MSNs tsa dorsal striatum (Kreitzer le Malenka, 2007), mofuta ona oa polasetiki o hlalositsoe ho li-neuron tsa D1R le tsa DR2 tsa tsela tse tobileng le tse sa tobang ho litoeba tsa BAC transgenic (Wang et al., 2006). Tlhaloso e le 'ngoe e ka bang teng bakeng sa tlhahiso ea mofuta ona oa LTD ho li-MNS synapses tse sa hlahiseng D2R ke hore, ka mefuta ea sele, D2R-ho its'etleha ha tlhahiso ea LTD ha e ea otloloha, empa ho fapana le hoo ho itšetleha ka ts'ebetso ea D2Rs ka li-interinurons tsa cholinergic ( Wang et al., 2006).

Tlatsetso ea nako e telele ea ts'ebetso (LTP) lithetleng tse thabisang ho li-MSNs ka dorsal le ventral striatum ha e khetholloe, mme tlhaiso-leseling e fumanehang ho fihlela joale e phehisana khang le ho feta. bapisoa le striatal LTD ka lebaka la mefuta-futa ea protocol e sebelisitsoeng ho hohela mofuta ona oa polasetiki ke li-laboratories tse fapaneng. Ka dorsal striatum, ho kenella kahare ho LTP ho D1 MSN ho latela D1R, athe, ho D2 MSNs, mokhoa o ts'oanang oa polotiki ea synaptic o hloka ts'ebetso ea adenosine A2R (Shen et al., 2008; Pascoli et al., 2014a). Litsong tse ka kotloloho le tse sa tobang, ts'ebetso ea li-D1R le li-A2R, le ts'ebetso e kopanetsoeng ea li-NMDARs e lebisa ho phosphorylation ea DARPP-32 le MAPK tse amehang polelo ea LTP (Calabresi et al., 1992, 2000; Kerr le Wickens, 2001; Surmeier et al., 2014). Ka har'a ventral striatum, protocol ea High Frequency Stimulation (HFS) e etsa mofuta oa LTP o itšetlehileng ka ts'ebetso ea D1Rs empa eseng D2Rs (Schotanus le Chergui, 2008b). Ho khahlisang, mosebetsi o fetileng o bontšitse hore LTP e imetsoe ke bahanyetsi ba D1 le ba D2 ba fanang ka maikutlo a hore mofuta ona oa LTP o ipapisitse le khatello ea DA (Li le Kauer, 2004). Phuputso ea morao-rao, e sebelisang boits'oaetso ba sele, e tlaleha hore le ha HFS-LTP e kentsoe ho D1 le D2 MSNs, mofuta ona oa LTP o thibetsoe ke kalafo ea koae feela tseleng e otlolohileng (Pascoli et al., 2011b). Bangoli ba tšoaea mekhoa ea ho kenella le ea polelo ea PDP ena eo ho tlalehiloeng hore e ne e le NMDA le ERK tseleng. Boithuto ba nako e tlang bo hlokoa ho etsa lipatlisiso ka methati e ka tlase ho LTP tseleng e sa tsejoeng, le ho tšoaea mofuta ona oa polasetiki ea synaptic ka mokhoa o ikhethileng.

Karolo ea DA ho buseng polasetiki ea striatal e rarollotsoe ka ho sekaseka mekhoa ea Spike Time Dependent Plasticity (STDP) dorsal striatum. Ka bobeli ba D1 le D2 MSNs, polasetiki ea synaptic e latela melao ea Bahebania. LTP e hlile e kenella ha ts'ebetso ea postynaptic spiking e latela ts'ebetso ea synaptic (nako e nepahetseng), ha LTD e ratoa ha taelo e khutlisoa (nako e mpe). Ha e bapisoa le li-synapses tse ling, dorsal striatum, DA e bapala likarolo tsa bohlokoa ho khetholla letšoao la polasetiki ea synaptic. Tseleng e tobileng, nako e nepahetseng e fana ka phaello ea PDP feela ha D1 e hlohlelletsoa, ​​ho seng joalo e lebisa ho LTD. Sebakeng seo, linako tse mpe tsa nako li etsa hore LTD ha li-D1R li se ke tsa khothatsoa. Tseleng e sa tobang, lets'oao la D2 lea hlokahala bakeng sa LTD ha ho ts'oaroa ha postynaptic ho lateloa ke ts'usumetso ea synaptic. Ha li-D2R li koetsoe 'me li-A2R li hlohlelletsoa, ​​protocol e tšoanang ea pairing e etsa hore ho be le LTP (Shen et al., 2008). Ka hona, modular ea DA ho dorsal striatum e netefatsa hore bateauctional ea synaptic ea polasetiki e latela melao ea Bahebber. Patlisiso e 'ngoe ea hlokahala ho bona hore na melao ena e sebetsa ho tsohle tse kenyellelitsoeng le ho kenella ka har'a moeaoo.

Lefu la Parkinson

Lefu la Parkinson's PD (physopathology) le hokahantsoe le ho putlama ho atileng ha li-neurons tse emisang DA - substantia Nigra pars compacta (SNpc), ka tahlehelo ea DA e fihlelang merero ea "striatal projeke neurons" (Obeso et al. 2010). Ho fokola ha tsela ea nigrostriatal dopaminergic ho lebisa ho liphetoho tsa bohlokoa tsa morphological le tšebetsong ho potoloho ea methapo ea methapo, ho kenyelletsa le liphetoho tsa sebopeho sa corticostriatal glutamatergic synaptic (Sgambato-Faure le Cenci, 2012; Mellone le Gardoni, 2013) le tahlehelo e latelang ea "striatal synaptic plasticity" (Calabresi et al., 2014). Phuputso e ntle haholo e bontšitse asymmetry ea phello ea kahlolo ea DA mabapi le khokahano ea li-striatonigral le striatopallidal MSNs (Day et al., 2006). Ka ho khetheha, ho fokola ha DA ho lebisa ho fokotseheng ho tebileng ha methapo ea dendritic le li-glutamatergic synapses ho li-striatopallidal MSNs empa eseng ho li-striatonigral MSNs (Day et al., 2006).

Haufinyane ho bontšitsoe hore li-degrees tse khetholloang tsa karohano ea DA li ama ka mokhoa o fapaneng mokhoa oa ho kenella le tlhokomelo ea mefuta e 'meli e fapaneng le e fapaneng ea corticostriatal synaptic plasticity (Paillé et al., 2010). Karolo ea nigral e sa phethahalang (e ka bang 75%) ha e ame corticostriatal LTD ho li-MSN, leha ho le joalo e felisitsoe ke lesion e felletseng. Sephetho sena se bonts'a hore tekanyetso e tlase haholo leha e le ea bohlokoa ea DA e hlokahala bakeng sa mofuta ona oa polasetiki ea synaptic. Ka lehlakoreng le leng, kahlolo e sa phethahaleng ea DA e feto-fetoha ka tsela e makatsang ts'ebetso ea ts'ebetso ea PDP ho li-MSN, e bonts'a karolo ea bohlokoa ea mofuta ona oa polasetiki ea synaptic matšoao a mantlha a parkinsonian motor (Paillé et al., 2010). Mefuteng e 'meli e fapaneng ea PD Shen et al. (2008) e bonts'itse hore ho li-MSNs tse hlalosang D2R, LTP ha ea thetsoa feela ke protocol e tloaelehileng ea ho paka empa hape le protocol e netefalitsoeng e tsejoang ho susumetsa LTD. Ka lehlakoreng le leng, ho D1R e hlahisang li-MSNs protocol e atisang ho ts'oara LTP e hlahisa mofuta o tiileng oa LTD o neng o le hlokolosi ho CB1 receptor block (Shen et al., 2008). Boemo pakeng tsa ts'ebetso ea neural ka kotloloho tseleng e sa tobang e bontšitsoe e le ketsahalo e kholo e bakiloeng ke bofokoli bo matla ba koloi bo bonoang ho PD (Calabresi et al., 2014). Mefuteng ea PD, eCB-Mediated LTD ha e eo empa e pholosoa ke kalafo ka D2R receptor agonist kapa ka li-inhibitors tsa ho senyeha ha eCB (Kreitzer le Malenka, 2007), ka hona e bonts'a khatello ea maikutlo ea eCB-Mediated ea tsela e sa tsamaisaneng ea tsela e sa tsamaelaneng e le sebapali sa bohlokoa taolong ea boitšoaro ba makoloi ho PD.

Liphetoho tsa sebopeho sa subNit ea NMDAR ho li-synapses tsa MSN li tlalehiloe ho tšehetsa polelo ena e fetotsoeng ea polasetiki (Sgambato-Faure le Cenci, 2012; Mellone le Gardoni, 2013). Hoa tsebahala hore li-NMDAR li tšoauoa ke GluN2A le GluN2B li-subunits tsa taolo tsa GNNX, e le GluN2B e ngata haholo (Dunah le Standaert, 2001). Haholo-holo liphetoho tse etsahallang li-synaptic NMDAR GluN2A / GluN2B subunit ka karolelano ea litaba tsa metsamao ea mantlha tsa MSN le taolo ea boitšoaro bo bobe ba koloi e bonoang mohlaleng oa rat oa PD (Picconi et al., 2004; Gardoni et al., 2006; Mellone le Gardoni, 2013). Haholo-holo, maemo a GluN2B a ile a fokotsoa ka ho khetheha likaroloana tsa synaptic ho tloha ho likhoto tse nang le 6-OHDA ka botlalo ha li bapisoa le likhoto tse sebetsanang le sham ha ho se na liphetoho tsa GluN2A ka har'a disampole tse tšoanang (Picconi et al., 2004; Gardoni et al., 2006; Paillé et al., 2010). Ntle le moo, mohlaleng oa 6-OHDA oa PD, likhoto tse nang le lesapo le ts'oanang la tsela ea nigrostriatal (hoo e ka bang 75%) li bonts'itse keketseho e kholo ea GluN2A immunostuning ea synode ntle le liphetoho tsa GluN2B (Paillé et al., 2010). Ka kakaretso lintlha tsena li bonts'a tekanyo e ntseng e eketseha ea GluN2A / GluN2B maemong a fapaneng a kahlolo ea DA maemong a liteko a PD. Ka hona, peptide e amohelang sele e kenang pakeng tsa tšebelisano lipakeng tsa GluN2A le protheine ea protheine ea PSD-95 e khona ho fokotsa maemo a synaptic a NMDAR e nang le li-NMDAR le poloko ea polypological NMDAR le li-synaptic proteinity ho li-MSNs (Paillé et al. , 2010). Ho feta moo, ts'usumetso ea D1Rs ka tsamaiso ea SKF38393 e hlophisa sebopeho sa subunit ea NMDAR mme e ntlafatsa boits'oaro ba koloi ka mohlala oa PD ea pele e theha khokahano e matla pakeng tsa sehlotšoana se ikhethileng sa li-receptors tsa DA le NMDAR le lits'ebetso tsa makoloi (Paillé et al., 2010).

Ka kakaretso, setšoantšo se hlahang sa pathophysiological se bonts'a hore matla a lipontšo tsa glutamatergic ho tloha cortex ho isa striatum a ka laoloa ka matla ke tekanyo e fapaneng ea kahlolo ea DA nakong ea kholo ea lefu lena (Setšoantšo. (Figure2) .2). Ebile, liphetoho tse tlisoang ho corticostriatal synaptic polasetiki li laoloa ka mokhoa o matla ke boemo ba nigral denervation bo susumetsang maemo a mokha oa DA le kopano ea li-NMDAR tsa Sgambato-Faure le Cenci, 2012).

Setšoantšo sa 2  

Liphetoho tsa limolek'hule le tšebetso ho glutamatergic synapse ho lefu la Parkinson le Huntington. Cartoon e bonts'a phapang ea glutamatergic corticostriatal synapse (phanele e ka letsohong le letšehali) le liphetoho tsa limolek'hule le tse sebetsang ho DA le NMDA ...

Lefu la Huntington

Lefu la Huntington (HD) ke lefu le tsoelang pele la neurodegenerative le tšoauoang ke chorea, ho fokotseha hoa kelello, le mathata a kelello. Liphetoho maemong a DA le DA ho receptor bokong li kenya letsoho mathateng a kalafo a HD (Spokes, 1980; Richfield et al., 1991; Garrett le Soares-da-Silva, 1992; van Oostrom et al., 2009). Ka ho khetheha, liphetoho tse itšetlehileng ka nako ea ho saena ha DA li amana le liphetoho tse ling tsa tšebetso ea glutamatergic synapse (Cepeda et al., 2003; Joshi et al., 2009; André et al., 2011a). Tumellanong le ts'ebetso ena ea biphasic, Graham et al. (2009) e bonts'itse hore monyetla oa ho ba mothating oa ho khothala ho latela maemo a NMDAR ho mefuta ea lipanya tsa HD e ne e kopantsoe le botebo ba sethala sa bona sa matšoao. Ka lehlakoreng le leng, litoeba tsa HD ke sa le monyane li bonts'a kutloisiso e ntlafalitsoeng ea maikutlo liketsahalong tse its'epileng tsa NMDAR ha li bapisoa le liphoofolo tsa mofuta oa hlaha. Ka lehlakoreng le leng, litoeba tsa khale tsa matšoao a HD li loantšoa le ho feta ke li-neurotoxicity tsa NMDA (Graham et al., 2009).

Ho se sebetse hantle le tahlehelo ea li-stNatal tsa MSN li bontša karolo ea mantlha ea lefu lena (Martin le Gusella, 1986). Le ha mekhoa e hlalosang phello e ikhethileng ea li-MSN ho HD e e-so rarolloe, litlaleho tse 'maloa li tsamaisana le ts'ebetso e sa tloaelehang ea phetiso ea lefu la dopaminergic le glutamatergic ho kenyellelitsoeng lefung la li-stNatal MSNs (Charvin et al., 2005; Fan le Raymond, 2007; Tang et al., 2007).

Ho fokotseha ha D1R le D2R ho striatum ho tsoa ho postmortem HD akili ho tlalehiloe lithutong tse 'maloa (Joyce et al., 1988; Richfield et al., 1991; Turjanski et al., 1995; Suzuki et al., 2001). Ntle le moo, phetoho e kholo ea methapo ea D1R le D2R le tšebetso ho striatum li hlalositsoe mehlaleng ea litoeba tsa HD (Bibb et al., 2000; Ariano et al., 2002; Paoletti et al., 2008; André et al., 2011b). Boithuto bo entsoeng ho lisele tsa "striatal cell" tse entsoeng ka HD li bonts'itse hore ho ts'oaroa ha lits'usumetso tsa phetoho e ntlafatsa lefu la lisele ka ts'ebetso ea D1R empa eseng D2R (Paoletti et al., 2008). Haholo-holo, ho qhekella le NMDA ho ekelitse lefu la lisele tse hlahisoang ke D1R empa li se ke tsa fana ka maikutlo a hore li-NMDAR li baka kotsi ea ho senyeha ha lisele tsa HD ho kotsi ea DA (Paoletti et al., 2008). Ho khahlisang, ketsahalo ea Cdk5 e fetelletseng e kenella ho sensitivityity ea lisele tsa HD tsa striatal ho DA le liphetho tsa glutamate (Paoletti et al., 2008). Tumellanong le lintlha tsena, Tang et al. (2007) e tlaleha hore glutamate le DA li sebetsa ka mokhoa o kopaneng oa ho susumetsa Ca e phahameng2+ matšoao le ho susumetsa apoptosis ea li-MSN ka litoeba tsa HD. Hape, litla-morao tsena li khethiloe ka boomo ke D1R eseng ke D2Rs (Tang et al., 2007). Leha ho le joalo, karolo ea D2R ea ho khelosa ho senyeha ha MSN e behiloe pele (Charvin et al., 2005, 2008), ka hona ho phahamisa khopolo-taba ea hore ts'ebetso ka bobeli ea D1R le D2R li ka kenya letsoho ho chefo ho glutamate / DA. Haufinyane tjena, André et al. (2011b) e bonts'itse, qalong, tokollo ea glutamate e ne e eketsoa liseleng tsa D1R ha e ntse e phahamisoa liseleng tsa D2R ka litoeba tsa HD. Haholo, qetellong, phetisetso ea glutamate e ne e fokotsehile ho lisele tsa D1R feela. Ka kakaretso, phuputso ena e fana ka maikutlo a hore liphetoho tse ngata li etsahala liseleng tsa D1R ho feta liseleng tsa D2R, ka linako tsohle tsa presymptomatic le matšoao. Qetellong, tumellanong le thuto ena, Benn et al. (2007) e bontšitse hore liperesente tsa lisele tse ntle tsa D2R ha li fetoloe le phenotype kapa lilemo. Leha ho le joalo, e tlameha ho tsotelloa hore liphetho tsena li emela ho se lumellane ho hlakileng ka lithuto tsa pele tse bontšang ho ba kotsing ea D2R e phahameng ho HD (Reiner et al., 1988; Albin et al., 1992). Ka hona, ho hlokahala liphuputso tse ling bakeng sa semelo se felletseng le kutlwisiso ea liphetoho tsa D1R vs. D2R ho HD.

Liphetoho ho tsa tikoloho ea li-synaptic vs. extra-synaptic ea li-NMDAR le tsona li bohlokoa bakeng sa ho pholoha ha neuronal ho HD (Levine et al., 2010). Ka ho khetheha, keketseho e ikhethileng ea li-NMDAR tse nang le li-NMDAR tse amanang le keketseho ea peiso ea extrasynaptic NMDAR e hlalositsoe mefuteng e fapaneng ea liphoofolo tsa HD (Zeron et al., 2004; Milnerwood et al., 2010). Ntle le moo, fantotoxicity e kopantsoeng le GluN2B-e nang le li-NMDARs e mpefalitse le ho fetoha ha li-MSN ka mokhoa oa knockin HD (Heng et al., 2009).

DA le glutamate cross-talk li bonahala li na le karolo ea bohlokoa ho aberrant synaptic plasticity e hlokometsoeng mefuteng ea liphoofolo tsa HD. RAP e itšetlehileng ka DAP, empa eseng LTD, ho dorsal striatum e fokotsehile ho R6 / 2 modelling ea mouse ea HD (Kung et al., 2007;; Setšoantšo Figure2) .2). Ho khahlisang, bofokoli ho LTP le polasetiki ea nakoana e bonoang mehlaleng ea liphoofolo ea HD li khutlisetsoa kalafo ka D1R agonist SKF38393 (Dallérac et al., 2011).

lemalla ntho e

Polasetiki e hlahisoang ke lithethefatsi ea "glutamatergic synapses" tsamaisong ea mesocorticolic e bile le tšusumetso haholo boits'oarong bo lemaletseng (Luscher le Bellone, 2008) and DA neurons ea VTA ke ntlha ea ho kopana eo ho eona lithethefatsi tse lemalloang li ka fetohang lipotoloho tsa boko (Brown et al., 2010). Propoto e hlahisoang ke lithethefatsi e hlahisitsoe e le phepelo e thabisang ho li-neuron tsa DA tsa VTA 24 h ka mor'a ho entoa ka setheo se le seng sa lithethefatsi tse lemalloang (Ungless et al., 2001; Bellone le Lüscher, 2006; Mameli et al., 2007; Yuan et al., 2013). Ho khahlisang ke hore e susumetsoa ke ts'ebetso ea li-D1 / D5R le NMDAR (Ungless et al., 2001; Argilli et al., 2008) hape e bontšoa ka ho kenyelletsa li-NMDARs tsa GluN3A (Yuan et al., 2013) le li-AMPAR tse haellang tsa GluA2 (Bellone le Lüscher, 2006). Ho feta moo, ho bontšitsoe hore ho abuoa ha li-receptor tsa glutamatergic tse hlahisoang ke koae ho VTA ho latela ketso ea koae ho transporter ea DA (DAT) le hore tšebetso ea DA ea neurons ka boeona e lekane ho susumetsa polasetiki ea evaptic ea evaptic e tsoang litlamong ho glutamatergic synapses (Brown et al., 2010). Ho supa D1 ho VTA hoa hlokahala bakeng sa liphetoho tsena tse fanang ka maikutlo a hore ho hokahana ha lets'oao la DAergic / glutamatergic ho VTA ho fetola potoloho maemong a synaptic.

Ho khahlisang, phetiso ea phetisetso ea glutamatergic ho VTA e lumelletse ponahalo ea polasetiki e ts'oaroang ke lithethefatsi ho NAc le boits'oaro bo latelang ba boitšoaro. Ka 'nete, ho tlosoa ha GluN1 ka mokhoa o khethiloeng ho li-neuron tsa DA tsa VTA ho felisa polasetiki e hlahisitsoeng ke koae ka bobeli ba NAc (Engblom et al., 2008) le ho thibela ho khutlisoa ha boipuso (Mameli et al., 2009).

Ho NAc, ho hokahana ha DA le glutamate kamora ho pepesetsoa ha koae ho thusa ho kenya boits'oaro bo bobebe ka ho tsamaisoa ha ho ts'oaroa ha AMPAR lits'ebetsong tse itseng tsa glutamatergic. Boithuto ba pejana bo fumane hore ts'usumetso ea D1R e eketsa polelo ea sebopeho sa GluA1 ka ts'ebetso ea PKA e nts'etsapele pele NMDA-e thehiloeng ke synaptic plasticity (Sun et al. 2005, 2008; Gao et al., 2006). Haufinyane, karolo ea ts'ebetso ea khoebo ea AMPAR ho polasetiki e kengoang ke lithethefatsi le sehokelo sa eona sa ho ikamahanya le boitšoaro e bontšitsoe. Ka 'nete, ho kenyelletsoa ha GluA2-tlhaile (GluA1 homomeric) AMPAR ho bontšitsoe ka bobeli kamora ho kenella litakatsong tsa cocaine le ho itaola ka mokhoa oa cocaine ka tlhahiso e thabisang ho li-MSNs ho NAc (Conrad et al., 2008; Lee et al., 2013; Ma et al., 2014; Pascoli et al., 2014b;; Setšoantšo Figure3) .3). Leha lithuto tsena li supa ho se lumellane ho mabapi le ho khetheha ha sele le se boletsoeng ka bohlophisi ba Ca2+ kenyelletso e kenelletseng ea AMPAR, ho tlosoa hoa li-receptors tsena ke mokhoa o sebetsang oa ho khutlisa mekhoa e lemalloang (Loweth et al., 2014; Pascoli et al., 2014b). AKa ho felletseng, lithuto tsena li bonts'a hore polelo ea boits'oaro bo bobebe e ipapisitse le ho fetoha ha letšoao la DA / glutamate le diphetoho tse tlisoang ke ho sebetsa hantle le boleng ba phetiso e thabisang ea synaptic.

Setšoantšo sa 3  

Liphetoho tsa Synaptic ho li-synapses tsa glutamatergic nakong ea ho tsuba koae. Cartoon e bonts'a phapang ea glutamatergic corticostriatal le hippocampastriatal synapses (phanele e ka letsohong le letšehali) le phetoho ea li-synaptic maemong a thabisang a li-MSNs nakong ea ...

Mekhoa e tlatselletsang ea tšebelisano lipakeng tsa glutamate le Sisteme ea DA ho NAc tlatsong ea lithethefatsi ke efe? Boithuto bo bongata bo bontšitse hore likarabo tse fapaneng tsa boitšoaro le molek'hule tse ts'oaroang ke koae li itšetleha ka tšebelisano ea D1R-NMDAR e laolang tšebetso ea litsela tsa ERK le taolo ea gene, polasetiki le boitšoaro (Girault et al., 2007;; Bertran-Gonzalez et al., 2008; Pascoli et al., 2014a). Ho khahlisang, ts'ebetso ea ts'ebeliso ea koae ea cocaine tseleng ea ERK e lekantsoe ho D1 MSNs mme e itšetlehile ka ts'ebetso e kopaneng ea D1 le NMDAR. Ho feta moo, blockade e tobileng ea ERK e bontšang e hlahisoang ke koae e thibela polelo ea boikhethelo ba sebaka (CPP; Valjent et al., 2000), sensomization ea locomotor (Valjent et al., 2006) le polasetiki e hlahisitsoeng ke lithethefatsi (Pascoli et al., 2011b; Cahill et al., 2014). Ho netefatsa karolo ea ts'ebelisano ea DA / glutamate ts'ebetsong ea ERK e hlahisang koae, ho boetse ho bontšitsoe hore thibelo e sa tobang ea tsela ea ERK e thibela mekhoa e lemalloang. Cocaine e kenya tšebetsong tyrosine kinase Fyn eo, ka phosphorylation ea GluN2B, potentiates Ca2+ tšusumetso ho tsoa ho li-NMDAR le ho kenya letsoho ho saena ha ERK. Ho khahlisang, thibelo ea Fyn e thibela ts'ebetso ea ERK ea koae ha e ntse e thibela thibelo ea GluN2B e nang le NMDAR impairs sensomization le CPP (Pascoli et al., 2011a). Ntle le moo, blockade ea D1 / GluN1 e ts'oanang le litselana tse tlase, leha e boloka ts'oaetso e le 'ngoe, e thibela li-D1 tse hlahisitsoeng ka bobeli tsa Ca2+ tšusumetso ka NMDAR le ts'ebetso ea ERK. Ka lebaka leo, maikutlo a boitšoaro a senyehile (Cahill et al., 2014).

Nahanisisa

Tšebelisano e sebetsang pakeng tsa DA le li-glutamate receptors e hlophisa mesebetsi e mengata e fapaneng bokong, mme ha e sa sebetse, e baka mathata a mangata a tsamaiso ea methapo. Haholo-holo puisano e kopaneng ea sefapano lipakeng tsa DA le li-receptors tsa glutamate li bapala karolo ea bohlokoa taolong ea makoloi, tlhokomeliso ea kelello le mohopolo, mathata a neurodegenerative, schizophrenia le boits'oaro bo lematsang. Ka hona, palo e kholo ea lithuto, tse hlalositsoeng tlhahlobisong ea hona joale, li entsoe ka sepheo sa ho utloisisa lits'oants'o tsa limolek'hule le tšebetso tse hokahanyang mesebetsi ea li-glutamate le li-receptors tsa DA. Ka ts'epo, tsebo e felletseng ea ho hlohlona ha glutamate le ho tšoaetsoa ke DA joalo ka Parkinson, Huntington le mafu a amanang le bokhoba, e ka emela mohato oa pele oa ho tsebahatsa le ho theha mekhoa ea ho phekola e ncha bakeng sa mathata ana a boko.

Khohlano ea polelo ea thahasello

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

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