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Pls nyem qhov no mus rau Part 1

Pls nyem qhov no mus rau Ntu 3

Cistanche cistanche hmoov cov txiaj ntsig kev noj qab haus huv --neuroprotective effect

4.3. Regulatory Mechanisms ntawm Dendrite Arborisatin thiab txha caj qaum tsim

Actin thiab microtubule bundling thiab reorganization yog cov caj qaum ntawm dendritic arborization, txhawb plasma membrane expansion. Actin nyob ntawm ntug ntawm dendrites thiab tsav kev tshawb nrhiav kev ua haujlwm. Microtubules tsim qhov chaw ntawm lub dendritic ncej thiab sib sau ua ke cov ncej tshiab no. Lub dynamic txheej txheem ntawm extension, branching, retraction, raws li zoo raws li orientation ntawm ceg, yog sib koom tes los ntawm ntau yam signaling mechanisms. Cov kev taw qhia cov txheej txheem no tau piav qhia meej los ntawm lwm tus kws sau ntawv (saib kev tshuaj xyuas los ntawm [1–3]) thiab yuav muab sau tseg ntawm no thiab hauv Table 1.

Actin monomer polymerization tso cai tsim cov actin filaments, stabilized los ntawm microtubules, uas txhawb nqa axonal thiab dendritic ceg expansion los ntawm thawj actin thaj ua rau thaj (saib xyuas los ntawm [1]). Actin thiab microtubule kev sib cuam tshuam lawv tus kheej yog ruaj khov los ntawm kev sib txuas cov proteins xws li microtubule-actin cross-linking factor (MACF1; [94]). Thaum microtubule ntxeem tau ntawm fillipodia txhawb cov ceg tsim, kev tshem tawm ntawm microtubules, tswj los ntawm ubiquitin-protein ligase 3a (Ube3a, tseem hu ua E6AP ubiquitin-protein ligase), sib npaug rau kev thim rov qab ntawm cov ceg dendritic [95]. Lub dynamic extension thiab reorganization ntawm dendritic ceg yog ib tug heev kev ua si-dependent txheej txheem; Yog li, qhov no tuaj yeem cuam tshuam los ntawm cov txheej txheem uas cuam tshuam rau ATP ntau lawm. Raws li ib qho piv txwv, kev cuam tshuam ntawm Drp-dependent fission yuav inhibit qhov tsim ntawm mitochondria me me kom txav mus rau hauv cov ceg dendritic thiab tau pom tias ua rau muaj qhov tsis zoo ntawm thawj ceg hauv nas Purkinje hlwb hauv lub cerebellum (hauv vivo thiab hauv vitro. Ib.) [96]. Kev hloov pauv hauv microtubule kev thauj mus los kuj tuaj yeem cuam tshuam cov ceg los ntawm kev hloov pauv lub peev xwm rau cov koom haum actin thiab microtubule (xws li, [97]). Muaj feem xyuam, muaj kev vam khom ntau ntawm kev txhais cov protein; Yog li ntawd, kev hloov pauv hauv mRNA thauj thiab kev txhais cov protein hauv zos kuj cuam tshuamneuronalarborization (saib los ntawm [98]). Ntawm qhov kev ceeb toom, cov noob tsis yooj yim X kev puas siab puas ntsws 1 (Fmr1, cov noob feem ntau cuam tshuam hauv cov kab mob X tsis yooj yim) yog ib qho tseem ceeb ntawm cov neeg txhais lus hauv zos mRNA hauv dendrites (saib xyuas los ntawm [99]).

Table 1. Extrinsic regulators ntawm dendritic arborization thiab txha caj qaum.

Cov ntawv luv: Slit1-Slit guidance ligand 1, Epah7-ephrin receptor A7, Sema3A-semaphorin 3A, NGF-nerve growth factor, BDNF- hlwb-derived neurotrophic factor, NT-neurotrophin, IGF1-insulin-like growth factor 1, Hpatocyte 1, Kev loj hlob zoo tshaj 1, Rac—Rac tsev neeg 1 me GTPase 1, Cdc42-cell division voj voog 42, TrK-tyrosine kinase receptor, CREST-calcium-responsive transactivator, CaMKIV- calmodulin-dependent protein kinase IV, CREB-cAMP- teb cov ntsiab lus protein ntau.

Extrinsic regulators ntawm arborisation suav nrog kev sib cuag-kev taw qhia (cell-to-cell los yog nrog cov extracellular matrix), secreted chemoattractant los yog chemorepellent molecules, thiab loj hlob yam. Protocadherins yog ib tsev neeg loj ntawm cov molecules, txawm li cas los xij, yuav tsum koom nrog kev sib cuag-kev tswj hwm ntawm dendritic arborization (thiab axonal extension). Clustered protocadherins tau pom tshwj xeeb los tswj arborization ntawm kev taw qhia los ntawm Rho GTPases (saib xyuas los ntawm [100]). Ib qho kev hloov pauv ntawm y-protocadherins hauv lub hlwb nas ua rau muaj kev cuam tshuam dendritic nyuaj, txawm hais tias cov txiaj ntsig ntawm qhov no feem ntau kuj lig hauv kev loj hlob cortical, los ntawm P18 txog P28 [67]. Qhov cuam tshuam rau hnub nyoog ncua sij hawm no yog qhov nthuav tshwj xeeb vim tias cov protocadherins kuj tau pom los tswj dendrite tus kheej zam hauv arbors, qhov tshwm sim uas tau hais meej meej los ntawm P12 [69]. Lwm cov proteins tswj cov cell-rau-cell tiv tauj uas cuam tshuam rau dendritic arborization muaj xws li dystroglycan, contactin 4 (CNTN4), thiab neurexin (NRXN)-neuroligin (NRLG) kev sib cuam tshuam. Dystroglycan, ib qho extracellular matrix protein, tau pom tias yuav txhawb kev loj hlob ntawm dendritic arbours hauv nas hippocampal.neuronsnyob rau hauv vitro nyob rau hauv ib tug yam ntxwv nyob ntawm lub cell division tswj protein 42 (Cdc42) GTPase [70]. CNTN4, ib qho protein txuam nrog schizophrenia thiab feem ntau pom los hloov synaptic muaj nuj nqi, kuj tau pom los tswj arborization ntawm hippocampal.neuronshauv tsev [101] Txawm li cas los xij, nyob rau hauv cov ntaub ntawv no, cov nyhuv yog me me, tej zaum yuav cuam tshuam lub luag hauj lwm tseem ceeb ntawm CNTN4 hauv synapse lub koom haum thiab, yog li ntawd, lub sij hawm lig uas nws ua nyob rau hauv txoj kev loj hlob. Neurexin thiab neuroligin yog adhesion proteins, uas yog feem ntau txuam nrog synaptic tsim vim lawv muaj feem ntawm axon terminals thiab dendritic spines. Nws tau pom nyob rau hauv nas lub hlwb hais tias kev sib cuam tshuam ntawm cov molecules no yog ib qho tseem ceeb rau thawj zaug stabilization ntawm synapses uas yuav tsum muaj kev ua ub no kom ruaj khov mus tas li [102]. Thaiv cov kev cuam tshuam no ua rau txo qis kev loj hlob ntawm dendritic arbor nrog rau kev tsim cov synapse tsawg [102].

Cov kws kho mob zais cia uas tswj hwm dendritic arborisation suav nrog semaphorin 3A (Sema3A), Slit guidance ligand 1 (Slit1) thiab ephrin A7 receptor (EphA7). Sema3A, uas yog chemorepellent rau axons, ua raws li ib tug chemoattractant rau dendrites, txhawb kev loj hlob thiab orientation ntawm thawj apical dendrite [74] thiab yog tsim nyog rau theem nrab thiab tertiary branching [75]. Slit1 yog lwm qhov zais cia, qhov no ua haujlwm los ntawm Robo receptor uas txhawb kev loj hlob dendritic thiab branching [71]. Interestingly, EphA7 zoo nkaus li yog lwm txoj cai molecule uas muaj cov teebmeem sib txawv thoob plaws hauv txoj kev loj hlob, raws li EphA7 signaling txwv kev loj hlob ntawm dendritic thiab thaum ntxov tus txha caj qaum thaum ntxov txoj kev loj hlob (ua ntej rau P10 nyob rau hauv tus nas) tab sis txhawb nqa dendritic txha nraub qaum tom qab kev loj hlob theem [54].

Tsev neeg ntawm cov teeb meem neurotrophic, suav nrog cov paj hlwb loj hlob (NGF), hlwb-derived neurotropic factor (BDNF), thiab neurotrophin-3 thiab -4 (NT-3, NT-4} ), uas muaj ntau lub luag haujlwm hauv kev tswj lub hlwb kev loj hlob thiab kev ua haujlwm, kuj tau raug txheeb xyuas tias ua rauneuronalarborisation thiab synapse tsim. Cov haujlwm ntawm BDNF hauv cov ntsiab lus no tau tshawb pom ntau tshaj plaws thiab pom los txhawb kev dendritic arborization, feem ntau ntawm kev ua kom lub tropomyosin receptor kinase (Trk) B receptor (TrkB, tshuaj xyuas kom meej los ntawm [56]). NT-3, ua los ntawm TrkC receptor, kuj tau pom los txhawb kev loj hlob ntawm arbor [81]. Mature BDNF thiab NT-3 ob leeg muaj kev nthuav qhia tshwj xeeb thiab tshwm sim los pab txhawb rau theem tom qab ntawm dendritic expansion. Hauv kev kawm zoo nkauj, Joo et al. (2014) qhia tias txo qis NT-3 signaling, muab los ntawm pre-synapticneuronsnyob rau hauv ib qho kev ua si-dependent yam, txo elongation ntawm dendrites los ntawm Purkinje neurons mus rau pial nto ntawm nas hlwb ntawm P7 thiab P14 (ua rau muaj kev cuam tshuam uas txuas ntxiv mus ntev) [81]. Txawm li cas los xij, lwm tus kws tshawb fawb tau pom lub peev xwm rau inhibition ntawm NT-3 los ntawm E21 rau P7 hauv nas kom ua rau cortical neurons nrog txo qis apical dendrites ntawm P7 [56], tawm tswv yim txog cov hnub nyoog tshwj xeeb tej zaum yuav txawv nyob ntawm lub paj hlwb cheeb tsam lossis NT-3 qhov chaw. Cov kev ua ntawm BDNF ntawm dendritic txoj kev loj hlob yog ib qho nyuaj rau cov ntsiab lus thiab tuaj yeem yog ob qho tib si tsim thiab ua haujlwm-nyob ntawm kev ua haujlwm [79]. Nws yog qhov zoo li tias lub molecule li pleiotropic li BDNF muaj ntau qhov sib txawv ntawm nws txoj kev taw qhia thiab kev taw qhia. Hauv kev txhawb nqa ntawm lub tswv yim no, nws tsis ntev los no tau pom, siv cov kab lis kev cai sib luag ntawm thawj nas neurons, uas BDNF los ntawm cov hom phiaj tom qab synaptic tuaj yeem khi rau TrkB receptors ntawm axons thiab simulate dendritic arborisation ntawm ib qho txawv thiab nyuaj intracellular signaling txoj kev [78 ]. Hepatocyte growth factor (HGF) kuj ua los ntawm nws cov tyrosine kinase receptor (Met nyob rau hauv cov ntaub ntawv no), yog ib qho tseem ceeb nyob rau hauv stimulating ntau yam kev loj hlob, thiab tau pom los txhawb dendritic kev loj hlob thiab branching [78,84]. Hepatocyte growth factor (HGF) kuj ua los ntawm nws cov tyrosine kinase receptor (Met nyob rau hauv cov ntaub ntawv no), yog ib qho tseem ceeb stimulating ntau yam kev loj hlob, thiab tau pom los txhawb dendritic kev loj hlob thiab branching [84]. Qhov no yog qhov txaus siab tshwj xeeb, raws li HGF, nrog rau ntau lwm yam kev loj hlob, tau pom tias txo qis hauv cov neeg mob ASD [86]. Ib yam li ntawd, neuregulins, cov tswv cuab ntawm tsev neeg epidermal growth factor (EGF), tau txuas rau kev hloov pauv synaptic muaj nuj nqi hauv cov kab mob neurological [86]. Raws li ib qho piv txwv, neuregulin 1 khi rau EGF receptor ErbB4 tau pom tias hloov pauv dendrite elaboration thiab synapse tsim hauv glutamatergic thiab qee qhov GABAergic thawj hippocampal.neurons[103].

Thaum cov kev taw qhia qis qis tsis tau tsim los rau txhua qhov kev tswj hwm sab hauv ntawm arborization, muaj ntau txoj hauv kev kom pom tseeb thiab sib cuam tshuam uas thaum kawg tswj hwm cov koom haum actin thiab microtubule. BDNF, piv txwv li, tau tsim zoo los hloov dendritic arborisation ntawm PI3K/Akt, cAMP teb-binding protein (CREB), thiab lwm cov noob teb thaum ntxov xws li Arc thiab Rho-GTPases (saib hauv [79]). Ras- thiab Rho-GTPases, ua ke nrog ntau cov protein kinases, piv txwv li, glycogen synthase kinase- 3 (GSK-3) thiab PI3K thiab CREB/CREB-binding protein (CBP) tuaj yeem suav hais tias yog tus tswv tswj hwm ntawm dendritic. arborisation (saib hauv [2]). Cov molecules no muaj kev cuam tshuam ntau heev thiab tuaj yeem cuam tshuam ncaj qha lossis cuam tshuam rau cytoskeletal rearrangement. Piv txwv li, nquag GSK-3 phosphorylates MACF1 hloov nws cov kev cuam tshuam nrog microtubules thiab f-actin nyob rau hauv cov npoo ntawm cov neurites txuas ntxiv [94]. Knockout thwmsim hauv nas qhia tias MACF1 yog ib qho tseem ceeb thoob plaws hauv txoj kev loj hlob, nrog knockout uas ua rau muaj coob tus ntawm cov thawj dendrites, tab sis ib tug txo dendritic ntev thiab txawv txav dendritic orientation thaum hloov nyob rau hauv txawv theem ntawm kev loj hlob nyob rau hauv vitro, raws li zoo raws li nyob rau hauv vivo [ 94] ib. Lwm txoj hauv kev ntawm kev hloov kho txoj hauv kev no, thiab, yog li ntawd, dendritic arborisation, yog los ntawm kev hloov pauv cov tswj hwm thiab chromatin hloov kho cov protein. ARD1B yog ib qho piv txwv ntawm chromatin tswj molecule uas cuam tshuam rau kev tsim cov cfos thiab Arc (ntawm phosphorylation ntawm CREB), thiab ntau txoj hauv kev downstream uas ua rau dendritic branching [55]. Cov teebmeem ntawm altering ARD1B binding nyob rau hauv nas hlwb (txo tus naj npawb thiab ntev ntawm apical thiab basal dendrites, muaj kev cuam tshuam loj heev nyob rau hauv pial contact, txo tus naj npawb thiab nce immaturity ntawm dendritic spines) yog complex, rereflecting cov kev ua ua ke ntawm cov kev [55].

Txawm hais tias ntau ntawm cov txheej txheem tau piav qhia saum toj no yog kev ua haujlwm-ywj siab, ib feem loj ntawm theem dynamic ntawm dendritic reorganization yog kev ua haujlwm-nyob ntawm seb. Kev taw qhia tom qab neurotransmitter tso tawm thiab khi yog qhov tseem ceeb rau kev ruaj khov dendritic kev loj hlob thiab txha nraub qaum thiab synapse tsim, nrog rau ntau qhov kev taw qhia thiab cov kab hauv qab tau piav qhia saum toj no tseem ceeb rau cytoskeletal reorganization entailed (saib hauv [2]). Sin et al. (2002) tau pom nyob rau hauv optic tectum ntawm Xenopus tadpoles uas lub teeb stimulation nce dendritic arborisation los ntawm ib tug mechanism uas koom nrog glutamate receptor signalling, ua rau txo RhoA kev ua si thiab nce Rac thiab Cdc42 signaling [89]. Interestingly, ib tug tom ntej kev kawm ntawm tus nas, siv maub rearing los tshawb txog kev ua si-dependant teebmeem ntawm dendritic arborisation, pom tau hais tias cov kev hloov zoo sib xws tab sis ntawm ib tug loj npaum li cas txo [89,104]. Qhov no qhia tau hais tias yuav muaj hom lossis thaj tsam ntawm lub hlwb sib txawv hauv kev koom tes ntawm kev ua haujlwm-nyob ntawm kev tswj lossis arborisation. Kev cuam tshuam nyob rau hauv cov txheej txheem ntawm neurotransmitter signaling yog, yog li ntawd, kom meej meej ib tug contributor rau neurological teeb meem. Kev hloov pauv ntawm ASD-tshwj xeeb kev hloov pauv ntawm GRIN2 (encoding GluN2B NMDA receptor subunit) mus rau hauv ib pawg neeg ntawm kab lis kev caineuronsnyob rau hauv lub xub ntiag ntawm wildtype GluN2B qhia tau hais tias txawm me me hloov nyob rau hauv lub xub ntiag ntawm cov noob tseem ceeb / cov protein muaj peev xwm cuam tshuam rau dendritic arborisation [104]. Hauv qhov piv txwv no, tsis muaj qhov hloov pauv tseem ceeb hauv thawj cov neurons, tab sis qhov txo qis hauv cov ceg ntoo, thiab txo qhov ntev ntawm ceg ntawm txhua theem ntawm tsob ntoo dendritic [104].

Txog rau tam sim no, kev tshawb fawb ntawm glial kev koom tes hauv kev ua tau zoo ntawm lub hlwb tau tsom mus rau cov teebmeem ntawm astrocytes thiab microglia ntawm qib synapse, tshwj xeeb tshaj yog tswj cov dendritic txha nraub qaum thiab cov qauv thiab synapse tsim, plasticity, thiab kev ua haujlwm. Muaj cov pov thawj tseem ceeb uas astrocytes cuam tshuam rau kev tsim synapse los ntawm kev sib xyaw ntawm kev sib cuag-nyob ntawm cov txheej txheem thiab cov khoom zais cia, suav nrog thrombospondin, cholesterol thiab ApoE, hevin, hloov pauv kev loj hlob (TFG)-, thiab chondroitin sulphate proteoglycan (saib xyuas los ntawm [105,106]). Astrocyte-neuronalkev sib cuag, tswj los ntawm y-protocadherin, zoo li yog qhov tseem ceeb rau kev yooj yim rau cov theem pib ntawm synapse tsim [68]. Secreted BDNF zoo nkaus li yog tus tsav tsheb loj ntawm microglial-influenced dendritic spine tsim, thiab tseem muaj cov pov thawj ntawm microglial phagocytosis ntawm pre-thiab post-synaptic cov ntsiab lus raws li ib feem ntawm lub cev pruning ntawm ntau synaptic kev sib txuas, tshwj xeeb tshaj yog cov uas tsis muaj kev ua si ( tshuaj xyuas los ntawm [107]). Phagocytosis yog tswj los ntawm classical immune signaling systems, xws li chemokines (tshwj xeeb yog Cx3cr1) thiab ntxiv (xws li C3 thiab C1q; [107–110]). Qhov tseem ceeb, txawm tias dhau ntawm qhov kev tshuaj xyuas no, tseem muaj cov ntaub ntawv tseem ceeb txhawb lub luag haujlwm ntawm microglia thiab astrocytes hauv kev tswj hwm ntawm synaptic plasticity hauv cov neeg laus lub hlwb (saib xyuas los ntawm [106,107]). Cov ntaub ntawv txwv tsis pub muaj xws li seb cov hlwb glial no puas pab txhawb rau theem ua ntej ntawm kev txhim kho neuronal xws li dendritic arborization, txawm tias Yang li al. (2012) [82] tau qhia astrocyte-dependent dendritic arborization hauv nas hlwb. Interestingly, qhov kev tshawb fawb no tau qhia tias astrocyte knockout ntawm Fmr1 yog txaus los ua kom txo qis dendritic arborization, vim yog qhov ntau tshaj ntawm NT-3 [82]. Cov ntaub ntawv tsis ntev los no kuj qhia tias astrocytes yuav tswj tauneuronalarborization los ntawm lipoprotein receptor chav kawm A rov ua dua ntawm cov lipoprotein receptor tsawg-density receptor-related protein 4 (LRP4, [111]).

5. Muaj peev xwm tiv thaiv kev tswj hwm cov cuab yeej thiab cov tshuaj kho mob

5.1. Genetic Risk Factors Uas Hloov Neuronal Arborisation thiab Associate nrog Neurodevelopmental Disorders

Qhov ntau zaus ntawm dendrite thiab txha nraub qaum abnormalities nyob rau hauv neurodevelopmental disorders yog vim muaj ib tug sib tov ntawm genetic susceptibility thiab ib tug hloov ib puag ncig thaum lub sij hawm txoj kev loj hlob (tej zaum yuav cuam tshuam ib tug tshwj xeeb raug mob nyob rau hauv tej rooj plaub). Ntau qhov kev pheej hmoo ntawm caj ces cuam tshuam nrog cov kab mob neurodevelopmental disorders (thiab neurodegeneration) cuam tshuam nrog cov molecular regulators ntawm dendritic txoj kev loj hlob uas tau teev tseg saum toj no thiab tau muab sau tseg rau hauv Table 2. Cov kev sib raug zoo ntawm cov noob caj noob ces thiab neurodevelopmental disorders tshwm sim nrog chromosomal deletions / duplication (xws li, Methyl Cpp. khi protein 2, MeCP2; 22q13 thiab lwm yam); Txawm li cas los xij, raws li ntau cov noob raug cuam tshuam, neurobiology tuaj yeem nyuaj rau kev xaiv (saib hauv [112]). MeCP2 yog tus tswj hwm kev hloov pauv uas muaj qhov cuam tshuam tseem ceeb ntawm kev loj hlob ntawm lub hlwb. Cov teebmeem ntawm cov noob no yog koob tshuaj- thiab kev sib deev-raws li kev sib deev: Rett syndrome tshwm sim hauv cov poj niam nrog kev txo qis hauv MeCP2 [112-114], thiab kev sib tshooj ntawm cov noob ua rau muaj kev pheej hmoo ntawm ASD thiab kev tsis taus kev txawj ntse, feem ntau hauv cov txiv neej (saib xyuas hauv [113]). Nyob rau hauv cov nqe lus ntawm arborization, deficiency nyob rau hauv MeCP2 ua rau txo dendritic ceg, txha nraub qaum, thiab txawv txav morphology [113]. Interestingly, pro-inflammatory cytokine interleukin -1 tau pom tias muaj kev cuam tshuam nrog MeCP2 thiab cuam tshuam rau nws txoj haujlwm (saib xyuas los ntawm [115]), uas muaj peev xwm ua tau los ntawm cov noob caj noob ces thiab ib puag ncig muaj peev xwm cuam tshuam los ua kom muaj kev pheej hmoo ntawm neurodevelopmental teeb meem. .