Cell-type-specific Memory Consolidation Tsav Los ntawm Kev Tswj Kev Txhais Lus

Dr. Sonenberg pawg tau pab txhawb rau kev nkag siab txog kev tswj hwm kev txhais lus hauv kev kawm thiab kev nco. Nyob rau hauv ib tsab xov xwm xwm txheej tsis ntev los no, lawv tau tshaj tawm cov xovtooj ntawm tes-hom kev txhais lus tshwj xeeb tswj kev nco qab sib koom ua ke.1 Lub sijhawm ntev (LTP) tau lees paub tias yog ib qho ntawm cov qauv cellular tseem ceeb ntawm kev kawm thiab kev nco.

Nyem raucij dose rau kev txhim kho kev nco

Feem ntau, muaj ob yam ntawm LTP uas tau tsav los ntawm kev sib txawv stimulations thiab mechanisms. Cov theem pib ntawm LTP (E-LTP) thiab lub sijhawm luv luv (STM) tau tshwm sim rau lub sijhawm luv luv thiab yog ib ntus, vam khom feem ntau ntawm kev hloov pauv ntawm cov protein uas twb muaj lawm. Lub sij hawm lig ntawm LTP (L-LTP) thiab qhov tshwm sim mus sij hawm ntev (LTM) yog elicited los ntawm kev muaj zog thiab rov ua dua stimulation thiab yog nyob ntev, yuav tsum tau tshiab protein synthesis.2

Kev txo qis rau LTP induction tuaj yeem pab txhawb kev hloov pauv ntawm E-LTP mus rau L-LTP thiab ua rau kev nco ua ke. Yog li ntawd, kev txiav txim siab cov tshuab molecular tshwj xeeb tsav LLTP tsim yog qhov tseem ceeb rau kev nkag siab txog kev kawm thiab kev nco. Cov pab pawg Dr. Sonenberg yav dhau los tau tshawb pom tias eukaryotic pib qhov tseem ceeb 2 (eIF2), tus tswj hwm ntawm cov protein synthesis, yog ib qho kev hloov pauv ntawm STM thiab LTM.3.

Nyob rau hauv ib qho teeb meem tsis ntev los no ntawm Xwm hu ua "eIF2 tswj kev nco sib koom ua ke ntawm excitatory thiab somatostatin neurons", tib pab pawg ntxiv elucidated cell-type-specific mechanisms ntawm kev nco ua ke uas tau tsav los ntawm eIF2.1 eIF2 yog phosphorylatable tivthaiv ntawm eIF2 ternary complex, uas tsav kev pib txhais lus.

Hauv cov eukaryotes siab dua, eIF2 subunit tuaj yeem ua phosphorylated los ntawm plaub kinases raws li cov lus teb kev ntxhov siab (ISR), uas yog PERK, PKR, HRI, thiab GCN2 (Fig. 1a). Phosphorylated eIF2 (p-eIF2) ntawm Ser51 cuam tshuam kev txhais lus dav dav, thaum paradoxically upregulating ib subset ntawm mRNAs nrog rau sab saum toj qhib qhib cov ntawv nyeem xws li Atf4.

Ntawm qhov tod tes, phosphatase xws li GADD34 / PP1c thiab CREP / PP1c complexes tuaj yeem dephosphorylate eIF2 . 4 Kev kawm tuaj yeem txo qis p-eIF2 qib, muaj peev xwm los ntawm cov qauv siv tshuab uas muaj kev tswj hwm kev ua kinase, xws li GCN2, lub ntsiab eIF2 kinase hauv lub hlwb (Daim duab 1a). Kev tshawb fawb siv GCN2−/- nas pom tau tias muaj cov noob hloov pauv thiab txhim kho L-LTP, ua rau LTM tom qab ua haujlwm tsis muaj zog.

Thaum cov txheej txheem kev kawm, los ntawm kev txo qis GCN2 thiab yog li txo qis p-eIF2, tej zaum yuav muaj tsawg dua inhibition ntawm CREB-dependent gene transcription, pab txhawb L-LTP thiab ua rau lub cim xeeb consolidation.5 Hauv kev pom zoo nrog kev xav tias L-LTP yog nyob ntawm cov protein tshiab. synthesis thiab hais tias p-eIF2 suppresses kev txhais lus, Dr. Sonenberg pawg ntxiv pom tias p-eIF2 impairs LTM. Hauv qhov sib piv, inhibition ntawm p-eIF2 txhim kho LTM, 3 sib cav rau eIF2 raws li kev hloov pauv rau lub cim xeeb.

Txawm li cas los xij, cov nas uas muaj homozygous non-phosphorylatable Eif2a kev hloov pauv Ser51Ala tuag hauv 1 hnub tom qab yug.3 Yog li ntawd, nws yog ib qho tseem ceeb rau lub hom phiaj p-eIF2 tshwj xeeb kom tsis txhob muaj kev phiv tsis zoo. Hauv tsab xov xwm Nature tsis ntev los no, Sharma et al. qhia tias eIF2 pab txhawb kev nco sib koom ua ke, tshwj xeeb tshaj yog nyob rau hauv excitatory neurons thiab somatostatin (SST) qhia txog inhibitory neurons.1

Thaum pib ntawm tsab xov xwm no, cov kws sau ntawv pom tias p-eIF2 raug txo los ntawm kev kawm nquag hauv cov xov tooj ntawm tes tshwj xeeb, tshwm sim hauv excitatory thiab SST-expressing inhibitory neurons. Yog li ntawd, lawv tau sim qhov kev xav tias eIF2 tswj kev nco sib koom ua ke los ntawm kev txhais lus tswj hauv excitatory thiab SST ntxiv rau inhibitory neurons ntawm cell-type-specific tshem tawm ntawm p-eIF2 .

Txhawm rau kom ua tiav qhov kev tshem tawm zoo ntawm peIF2 yam tsis muaj kev tuag, txoj kev tshawb no tau siv cov nas hloov pauv uas nqa homozygous non-phosphorylatable Eif2a mutant Ser51- Ala thiab hom tsiaj qus Eif2a transgene flanked los ntawm lox sites (Eif2aA / A fTg plus ). Los ntawm kev hla Eif2aA/AfTg ntxiv rau nas nrog cov Cre-expressing nas sib txawv, p-eIF2 tau xaiv tshem tawm hauv excitatory neurons (hauv Eif2a cKICAmk2a nas), inhibitory neurons (hauv Eif2a cKIGad2 nas), SST ntxiv rau inhibitory neurons (hauv Eif2a cKISst nas), thiab parvalbumin (PVALB ntxiv) inhibitory neurons (hauv Eif2a cKIPvalb nas), feem.

Cov kws sau ntawv thawj zaug tshawb xyuas qhov cuam tshuam ntawm p-eIF2 tshem tawm ntawm kev nco ua ke hauv cov neurons excitatory. Thaum STM tsis cuam tshuam rau theem tus cwj pwm, LTM tau txhim kho ntau yam hauv Eif2a cKICAmk2a nas. Ib qho kev sim uas muaj tseeb uas txhaj AAV9-Camk2a-Cre rau hauv hippocampi ntawm Eif2aA/AfTg ntxiv rau cov nas kuj tau txhim kho LTM.

Cov kev tshawb fawb yav dhau los tau qhia tias p-eIF2 inhibits protein synthesis ntawm qib translational.4 Raws li xav tau, p-eIF2 tshem tawm hauv excitatory neurons txhim kho cov protein synthesis thiab ua rau muaj kev sib txuas lus zoo ib yam li cov txheej txheem kev kawm. Protein synthesis yog qhov yuav tsum tau ua ua ntej rau L-LTP, cov txheej txheem putative hauv qab LTM.

Raws li kev tshawb pom yav dhau los uas p-eIF2 cuam tshuam L-LTP, 3 p-eIF2 tshem tawm hauv excitatory neurons txhim kho excitatory inputs thaum txo qis inhibitory inputs, txhawb kev hloov ntawm E-LTP mus rau L-LTP. Ua ke, cov txiaj ntsig los ntawm peb qhov saum toj no qhia tau hais tias p-eIF2 tshem tawm hauv excitatory neurons txhim kho cov protein txhais lus hauv qab ntawm qhov induction ntawm L-LTP, yog li pab txhawb kev sib koom ua ke ntawm LTM (Fig. 1b).

Siv cov txheej txheem zoo sib xws, cov kws sau ntawv tau tshawb xyuas ntxiv txog qhov cuam tshuam ntawm p-eIF2 tshem tawm hauv inhibitory neurons. Lawv pom tias ablation ntawm p-eIF2 nyob rau hauv inhibitory neurons (hauv Eif2a cKIGad2 nas) los yog SST ntxiv rau inhibitory neurons (hauv Eif2a cKISst nas) ua rau muaj kev sib koom ua ke ntawm kev nco.

Tsis tas li ntawd, lawv tau tshaj tawm los ntawm kev sim electrophysiological uas p-eIF2 tshem tawm hauv SST ntxiv rau inhibitory neurons tuaj yeem txhawb kev nco txog kev sib koom ua ke los ntawm ob lub tswv yim: disinhibition ntawm excitatory neurons, yog li pab txhawb LTP induction thiab kev tawm tsam ntawm cov khoom siv los ntawm lub cev entorhinal. Txawm hais tias p-eIF2 tshem tawm hauv PVALB ntxiv rau inhibitory neurons kuj txhim kho kev txhais cov protein, nws tsis cuam tshuam rau LTP lossis LTM.

Zuag qhia tag nrho, qhov no yog thawj txoj kev tshawb fawb deciphering cell-type-specific mechanisms of memory consolidation controlled by eIF2 phosphorylation. Txhim kho kev txhais lus dav dav hauv excitatory neurons pab txhawb L-LTP kev qhia, thaum hloov pauv hauv SST ntxiv rau inhibitory neurons txhawb kev nco ntawm qib Circuit Court.

Ob hom neurons no tuaj yeem ua haujlwm sib raug zoo los pab txhawb kev nco ua ke (Daim duab 1b). Tsis tas li ntawd, eIF2 phosphorylation tshwm sim nyob rau hauv ntau yam kev ntxhov siab thiab kev puas siab puas ntsws; Yog li ntawd, kev nkag siab ntau ntxiv txog nws cov xov tooj ntawm tes-cov lus qhia tshwj xeeb thaum kawm thiab nco tuaj yeem muaj qhov cuam tshuam rau kev kho mob. Piv txwv li, p-eIF2 thiab peb qhov kev ntxhov siab teb kinases (PKR, PERK, GCN2) tau qhib rau hauv Alzheimer's tus kab mob, vim yog cov lus teb tsis tau tshwm sim los ntawm Aggregates, thiab tau oligomers.4

Qhov nce p-eIF2 tuaj yeem ua rau lub cim xeeb tsis zoo, ua rau lub voj voog tsis zoo. Txawm li cas los xij, phosphorylation ntawm eIF2 yog cov txheej txheem dynamic uas tuaj yeem thim rov qab los ntawm kev kawm nquag (Daim duab 1a). Nws implicates lub voj zoo ntawm kev kawm thiab kev nco: ntawm ib sab, kev kawm per se txhawb kev tsim LTM; ntawm qhov tod tes, mechanicistically, kev kawm txo qis p-eIF2, yog li pab txhawb kev sib koom ua ke ntawm LTM. Txoj kev tshawb no qhia tau hais tias cell-type-specific translational tswj los ntawm eIF2 phosphorylation yog ib qho tseem ceeb rau kev nco consolidation.

Fig. 1 Lub luag haujlwm ntawm eIF2 phosphorylation hauv kev nco ua ke. ib qho PERK, PKR, HRI, thiab GCN2 kinases tuaj yeem phosphorylate eIF2 thaum lub sij hawm integrated stress response (ISR); thaum phosphatase kev ua ntawm GADD34 / PP1c thiab CREP / PP1c complexes ua rau dephosphorylation. Kev kawm tuaj yeem txo eIF2 phosphorylation, ua rau muaj kev hloov pauv cov protein ntau ntxiv thiab pab txhawb kev nco ua ke. Kev hloov pauv ntawm kinase kev ua ub no, xws li kev txo qis GCN2 kev ua haujlwm, yog ib qho kev npaj ua haujlwm tom qab kev kawm txog kev txo qis ntawm p-eIF2 . 5 b Kev tshem tawm ntawm phosphorylated eIF2 (p-eIF2) hauv somatostatin (SST) neurons thiab excitatory neurons ua rau kev nco txog kev sib koom ua ke ntawm txoj hauv kev sib txawv. Hauv SST ntxiv rau cov neurons, ablation ntawm p-eIF2 ua rau muaj kev hloov pauv dav dav ntawm cov protein ntau, tsawg dua cov teeb meem inhibitory rau pyramidal neurons ntawm hippocampus, uas tuaj yeem txo qis qhov pib xav tau rau L-LTP induction ua rau thaum kawg ua rau kev nco mus ntev. Ablation ntawm p-eIF2 nyob rau hauv excitatory neurons ntawm hippocampus kuj txhim kho cov protein txhais lus, uas ua rau muaj zog excitatory inputs thiab txo inhibitory sawv daws yuav, uas txhim khu L-LTP thiab ua rau lub cim xeeb consolidation. Duab tsim nrog Biorender.com

Cistanche txhim kho kev nco li cas?

Cistanche yog tshuaj ntsuab ntxiv uas tau siv ib txwm siv hauv Suav tshuaj los txhawb kev noj qab haus huv thiab kev noj qab haus huv, suav nrog kev paub txog kev ua haujlwm. Cov kev tshawb fawb tau pom tias Cistanche muaj cov ntsiab lus uas tuaj yeem pab txhim kho kev nco thiab kev paub txog kev ua haujlwm los ntawm kev ua kom cov ntshav txaus thiab oxygen mus rau lub hlwb, txo qhov mob, thiab tiv thaiv lub hlwb los ntawm kev puas tsuaj los ntawm cov dawb radicals.

Ntxiv mus, Cistanche yog nplua nuj nyob rau hauv antioxidants, uas yuav pab txo tau oxidative kev nyuaj siab thiab txhim kho lub hlwb ua hauj lwm. Antioxidants pab neutralize dawb radicals thiab unstable molecules uas yuav ua rau puas cell membranes thiab lwm yam qauv nyob rau hauv lub hlwb. Zuag qhia tag nrho, qhov tseeb mechanism uas Cistanche txhim kho kev nco tsis tau nkag siab tag nrho, tab sis nws ntseeg tau tias yog vim nws lub peev xwm los txhim kho lub hlwb kev noj qab haus huv thiab kev ua haujlwm.

RTSEEM CEEB

1. Sharma, V. et al. eIF2 tswj kev nco ua ke ntawm excitatory thiab somatostatin neurons. Xwm Txheej 586, 412–416 (2020).

2. Kandel, ER Lub molecular biology ntawm kev nco cia: kev sib tham ntawm noob thiab synapses. Science 294, 1030–1038 (2001).

3. Costa-Mattioli, M. et al. eIF2 phosphorylation bidirectionally tswj kev hloov ntawm luv luv mus rau lub sij hawm ntev synaptic plasticity thiab nco. Cell 129, 195–206 (2007).

4. Moon, SL, Sonenberg, N. & Parker, R. Neuronal kev tswj hwm ntawm eIF2 muaj nuj nqi hauv kev noj qab haus huv thiab kev puas siab puas ntsws. Trends Mol. Med. 24, 575–589 (2018).

5. Costa-Mattioli, M. et al. Kev txhais lus tswj ntawm hippocampal synaptic plasticity thiab nco los ntawm eIF2 kinase GCN2. Xwm Txheej 436, 1166–1173 (2005).