recording-synaptic-plasticity-acute-hippocampal-slices-maintained

Recording Synaptic Plasticity in Acute Hippocampal Slices Maintained in a Small-volume Recycling-, Perfusion-, and Submersion-type Chamber System

Even though experiments on brain slices have been in use since 1951, problems remain that reduce the probability of achieving a stable and successful ...

Fudan University

&#x8FD1;&#x51E0;&#x5E74;&#x7684;&#x7279;&#x70B9;&#x662F;&#xFF0C;&#x5927;&#x91CF;&#x7684;&#x6F5C;&#x5728;&#x7684;&#x7A81;&#x89E6;&#x6838;&#x86CB;&#x767D;&#x4F7F;&#x8005;&#xFF0C;&#x88AB;&#x8BA4;&#x4E3A;&#x662F;&#x53C2;&#x4E0E;&#x53EF;&#x5851;&#x6027;&#x76F8;&#x5173;&#x57FA;&#x56E0;&#x7684;&#x8868;&#x8FBE;&#xFF0C;&#x800C;&#x4E14;&#x5177;&#x6709;&#x80FD;&#x529B;&#x7684;&#x79C9;&#x6301;-&#x4ECB;&#x5BFC;&#x548C;&#x6D3B;&#x6027;&#x4F9D;&#x8D56;&#x6838;&#x5BFC;&#x5165;&#x3002;&#x4E0D;&#x8FC7;&#xFF0C;&#x5F88;&#x4EE4;&#x4EBA;&#x60CA;&#x8BB6;&#x7684;&#x5B66;&#x4E60;&#x548C;&#x8BB0;&#x5FC6;&#x7684;&#x7EC6;&#x80DE;&#x6A21;&#x578B;&#x4E2D;&#x663E;&#x793A;&#x8FD9;&#x79CD;&#x86CB;&#x767D;&#x7684;&#x6838;&#x5BFC;&#x5165;&#x6570;&#x636E;&#x7F3A;&#x4E4F;&#x3002;&#x53EA;&#x662F;&#x6700;&#x8FD1;&#x624D;&#x53D1;&#x73B0;&#x5411;&#x6838;&#x8FC7;&#x5883;&#x7684;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x73AF;&#x78F7;&#x9178;&#x817A;&#x82F7;&#x53CD;&#x5E94;&#x5143;&#x4EF6;&#x7ED3;&#x5408;&#x86CB;&#x767D; 2 (CREB2) &#x671F;&#x95F4;&#x957F;&#x671F;&#x8427;&#x6761; (&#x6709;&#x9650;&#x516C;&#x53F8;)&#xFF0C;&#x4F46;&#x4E0D;&#x662F;&#x5728;&#x957F;&#x671F;&#x957F;&#x65F6;&#x7A0B;&#x589E;&#x5F3A; (LTP) &#x6D77;&#x9A6C;&#x795E;&#x7ECF;&#x5143;&#x7A81;&#x89E6;&#x4F20;&#x9012;&#x7684;&#x8FC7;&#x7A0B;&#x3002;&#x96C5;&#x5404;&#x5E03;&#x662F;&#x60C5;&#x4FA3; NMDA &#x53D7;&#x4F53;&#x6D3B;&#x6027;&#x7684;&#x6838;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x7684;&#x53E6;&#x4E00;&#x4E2A;&#x4F7F;&#x8005;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x6211;&#x4EEC;&#x65E8;&#x5728;&#x7814;&#x7A76;&#x662F;&#x5426;&#x96C5;&#x5404;&#x7D2F;&#x79EF;&#x6D3B;&#x52A8;&#x4F9D;&#x8D56;&#x7684;&#x7A81;&#x89E6;&#x53EF;&#x5851;&#x6027;&#x76F8;&#x5173;&#x7684;&#x751F;&#x7406;&#x6A21;&#x578B;&#x5728;&#x7EC6;&#x80DE;&#x6838;&#x4E2D;&#x3002;

&#x6838;&#x96C5;&#x5404;&#x7684;&#x6D77;&#x9A6C;&#x795E;&#x7ECF;&#x5143;&#x540E;&#x79FB;&#x4F4D;&#x523A;&#x6FC0;&#x8BF1;&#x5BFC;&#x957F;&#x65F6;&#x7A0B;&#x589E;&#x5F3A;&#xFF0C;&#x4F46;&#x4E0D;&#x662F;&#x957F;&#x671F;&#x8427;&#x6761;&#x3002;

In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity.

Nuclear translocation of jacob in hippocampal neurons after stimuli inducing long-term potentiation but not long-term depression.

Ces derni&egrave;res ann&eacute;es qu&#39;un certain nombre de messagers de prot&eacute;ines nucl&eacute;aires synapto potentiels ont &eacute;t&eacute; caract&eacute;ris&eacute; qui sont cens&eacute;es &ecirc;tre impliqu&eacute;s dans l&#39;expression des g&egrave;nes de plasticit&eacute;-connexes et qui ont la capacit&eacute; de l&#39;important - m&eacute;diation et d&eacute;pendante de l&#39;activit&eacute; nucl&eacute;aire importer. Cependant, il y a un manque surprenant de donn&eacute;es montrant l&#39;importation nucl&eacute;aire de ces prot&eacute;ines dans des mod&egrave;les cellulaires de l&#39;apprentissage et la m&eacute;moire. R&eacute;cemment, il a &eacute;t&eacute; constat&eacute; que la transcription factor AMP cyclique response element binding protein 2 (CREB2) transite vers le noyau au cours de la d&eacute;pression &agrave; long terme (DLT), mais pas au cours de la potentialisation &agrave; long terme (LTP), de la transmission synaptique dans des neurones hippocampal primaires. Jacob est un autre messager qui couple NMDA-r&eacute;cepteur-activity &agrave; l&#39;expression des g&egrave;nes nucl&eacute;aires. L&#39;&eacute;tude visait donc &agrave; &eacute;tudier si Jacob s&#39;accumule dans le noyau dans des mod&egrave;les physiologiques pertinents de la plasticit&eacute; synaptique d&eacute;pendante de l&#39;activit&eacute;.

Translocation nucl&eacute;aire de jacob dans les neurones de l&#39;hippocampe apr&egrave;s stimulus induisant la potentialisation &agrave; long terme mais pas &agrave; long terme d&eacute;pression.

In den letzten Jahren, die eine Reihe von potenziellen Synapto-nukleare Protein boten gepr&auml;gt haben, die man Plastizit&auml;t-bezogene Genexpression, und beteiligt, die die Kapazit&auml;t von importin - vermittelte und leistungsabh&auml;ngige nukleare importieren. Allerdings gibt es ein &uuml;berraschender Mangel an Daten zeigen den nuklearen Import solcher Proteine in zellul&auml;ren Modellen von lernen und Ged&auml;chtnis. Erst vor kurzem wurde festgestellt, dass das Transkription Faktor zyklischem AMP Antwort Element verbindliches Protein 2 (CREB2) zum Kern, w&auml;hrend langfristige Depression (LTD), aber nicht w&auml;hrend langfristige Erm&ouml;glichung (LTP) der synaptischen &Uuml;bertragung in prim&auml;ren Neuronen l&auml;uft. Jacob ist eine andere Messenger, der NMDA-Rezeptor-Aktivit&auml;t zu nuklearen Genexpression Paare. Wir wollten daher, ob Jacob im Zellkern in physiologischen relevanten Modelle der leistungsabh&auml;ngige synaptische Plastizit&auml;t sammelt zu studieren.

Nukleare Translokation von Jacob in Neuronen nach Reize induzierende langfristige Erm&ouml;glichung aber nicht langfristige Depression.

Negli ultimi anni un numero di potenziali messaggeri synapto-nucleare della proteina &egrave; stato caratterizzato che si pensiero siano coinvolti nell&#39;espressione genica plasticit&agrave;-correlati e che hanno la capacit&agrave; di importin - mediata e importare attivit&agrave;-dipendente nucleare. Tuttavia, c&#39;&egrave; una sorprendente scarsit&agrave; di dati visualizzando l&#39;importazione di tali proteine nucleare in modelli cellulari dell&#39;apprendimento e della memoria. Solo recentemente si &egrave; riscontrato che la trascrizione fattore AMP ciclico response element binding protein 2 (CREB2) transita al nucleo durante la depressione a lungo termine (LTD), ma non durante il potenziamento a lungo termine (LTP) della trasmissione sinaptica nei neuroni hippocampal primari. Jacob &egrave; un altro Messaggero che le coppie NMDA-recettori-attivit&agrave; di espressione del gene nucleare. Abbiamo quindi rivolto a studiare se Jacob si accumula nel nucleo in modelli fisiologici rilevanti della plasticit&agrave; sinaptica attivit&agrave;-dipendente.

Traslocazione nucleare di jacob nei neuroni hippocampal dopo stimoli che inducono fenomeni di potenziamento a lungo termine, ma non a lungo termine depressione.

&#x53EF;&#x5851;&#x6027;&#x95A2;&#x9023;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x3068;&#x8003;&#x3048;&#x3089;&#x308C;&#x308B;&#x6F5C;&#x5728;&#x7684;&#x306A; synapto &#x6838;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x4F7F;&#x5F92;&#x306E;&#x6570;&#x7279;&#x5FB4;&#x3065;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x6700;&#x8FD1;&#x306E;&#x5E74;&#x3067;&#x30A4;&#x30F3;&#x30DD;&#x30FC;&#x30C1;&#x30F3;&#x306E;&#x5BB9;&#x91CF;&#x304C;&#x3042;&#x308B; - &#x3092;&#x4ECB;&#x3057;&#x305F;&#x3057;&#x3001;&#x6838;&#x6D3B;&#x52D5;&#x4F9D;&#x5B58;&#x3092;&#x30A4;&#x30F3;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x643A;&#x5E2F;&#x96FB;&#x8A71;&#x306E;&#x30E2;&#x30C7;&#x30EB;&#x5B66;&#x7FD2;&#x3068;&#x8A18;&#x61B6;&#x306E;&#x3088;&#x3046;&#x306A;&#x86CB;&#x767D;&#x8CEA;&#x306E;&#x6838;&#x306E;&#x8F38;&#x5165;&#x3092;&#x793A;&#x3059;&#x30C7;&#x30FC;&#x30BF;&#x306E;&#x9A5A;&#x304F;&#x3079;&#x304D;&#x4E0D;&#x8DB3;&#x3067;&#x3059;&#x3002;&#x3054;&#x304F;&#x6700;&#x8FD1;&#x3001;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x30B5;&#x30A4;&#x30AF;&#x30EA;&#x30C3;&#x30AF; AMP &#x5FDC;&#x7B54;&#x8981;&#x7D20;&#x7D50;&#x5408;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA; 2 (CREB2) &#x306B;&#x6838;&#x9577;&#x671F;&#x6291;&#x5727; (LTD) &#x4E2D;&#x304C;&#x6D77;&#x99AC;&#x306E;&#x4E00;&#x6B21;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306B;&#x304A;&#x3051;&#x308B;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x4F1D;&#x9054;&#x306E;&#x9577;&#x671F;&#x5897;&#x5F37; (LTP) &#x4E2D;&#x3067;&#x306F;&#x306A;&#x304F;&#x9077;&#x79FB;&#x3053;&#x3068;&#x304C;&#x898B;&#x3064;&#x304B;&#x308A;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x30B8;&#x30A7;&#x30A4;&#x30B3;&#x30D6;&#x6838;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x3059;&#x308B; NMDA &#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x6D3B;&#x6027;&#x3092;&#x30AB;&#x30C3;&#x30D7;&#x30EB;&#x5225;&#x306E;&#x30E1;&#x30C3;&#x30BB;&#x30F3;&#x30B8;&#x30E3;&#x30FC;&#x3067;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x30E4;&#x30B3;&#x30D6;&#x6838;&#x6D3B;&#x6027;&#x4F9D;&#x5B58;&#x6027;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x53EF;&#x5851;&#x6027;&#x306E;&#x751F;&#x7406;&#x7684;&#x95A2;&#x9023;&#x6027;&#x306E;&#x9AD8;&#x3044;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x84C4;&#x7A4D;&#x3059;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x691C;&#x8A0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x76EE;&#x7684;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;

&#x30B8;&#x30A7;&#x30A4;&#x30B3;&#x30D6;&#x6D77;&#x99AC;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306B;&#x304A;&#x3051;&#x308B;&#x9577;&#x671F;&#x5897;&#x5F37;&#x3067;&#x3059;&#x304C;&#x306A;&#x3044;&#x9577;&#x671F;&#x7684;&#x306A;&#x4E0D;&#x6CC1;&#x306E;&#x8A98;&#x767A;&#x523A;&#x6FC0;&#x5F8C;&#x6838;&#x8EE2;&#x5EA7;&#x306F;&#x3002;

&#xCD5C;&#xADFC; &#xBA87; &#xB144;&#xAC04;&#xC774; &#xC18C;&#xC131; &#xAD00;&#xB828; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604;&#xC5D0; &#xAD00;&#xC5EC; &#xB420; &#xAC83;&#xC73C;&#xB85C; &#xC0DD;&#xAC01; &#xB418;&#xB294; &#xB2E4;&#xC591; &#xD55C; &#xC7A0;&#xC7AC;&#xC801;&#xC778; synapto &#xD575; &#xB2E8;&#xBC31;&#xC9C8; &#xBA54;&#xC2E0;&#xC800; &#xD2B9;&#xC9D5; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; importin&#xC758; &#xB2A5;&#xB825;&#xC744;&#xAC00;&#xC9C0;&#xACE0;-&#xC911;&#xC7AC; &#xBC0F; &#xD65C;&#xB3D9; &#xC885;&#xC18D;&#xC801;&#xC778; &#xD575;&#xC744; &#xAC00;&#xC838;&#xC62C;. &#xADF8;&#xB7EC;&#xB098;, &#xC774;&#xB7EC;&#xD55C; &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xD575; &#xAC00;&#xC838;&#xC624;&#xAE30; &#xD559;&#xC2B5; &#xBC0F; &#xBA54;&#xBAA8;&#xB9AC;&#xC758; &#xD734;&#xB300; &#xC804;&#xD654; &#xBAA8;&#xB378;&#xC744; &#xBCF4;&#xC5EC;&#xC8FC;&#xB294; &#xB370;&#xC774;&#xD130;&#xC758; &#xB180;&#xB77C;&#xC6B4; &#xC18C;&#xC218;&#xAC00; &#xC774;&#xB2E4;. &#xCD5C;&#xADFC; &#xC7A5;&#xAE30; &#xBD88;&#xD669; (&#xACF5;&#xC0AC;) &#xD558;&#xB294; &#xB3D9;&#xC548; &#xD558;&#xC9C0;&#xB9CC; &#xC7A5;&#xAE30; potentiation (LTP) hippocampal &#xAE30;&#xBCF8; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC5D0; &#xC2DC; &#xB0C5; &#xC2A4; &#xC804;&#xC1A1; &#xC911;&#xC774; &#xC544;&#xB2C8;&#xB77C; &#xC804;&#xC0AC; &#xC778;&#xC790; &#xC21C;&#xD658; &#xC570;&#xD504; &#xC751;&#xB2F5; &#xC694;&#xC18C; &#xBC14;&#xC778;&#xB529; &#xB2E8;&#xBC31;&#xC9C8; 2 (CREB2) &#xD575;&#xC744; &#xC804;&#xC1A1; &#xBC1C;&#xACAC;. &#xC57C; &#xACF1;&#xC774; &#xB2E4;&#xB978; &#xBA54;&#xC2E0;&#xC800; &#xD575; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604;&#xC5D0; NMDA &#xC218;&#xC6A9; &#xCCB4; &#xD65C;&#xB3D9;&#xC744; &#xCEE4;&#xD50C;. &#xC6B0;&#xB9AC;&#xB294; &#xB530;&#xB77C;&#xC11C; &#xC81C;&#xC774;&#xCF65; &#xC0DD;&#xB9AC; &#xAD00;&#xB828; &#xBAA8;&#xB378; &#xD65C;&#xB3D9;&#xC5D0; &#xC885;&#xC18D; &#xC2DC; &#xB0C5; &#xC2A4;&#xAC00; &#xC18C;&#xC131;&#xC758; &#xD575;&#xC5D0; &#xCD95;&#xC801; &#xC5EC;&#xBD80;&#xB97C; &#xC5F0;&#xAD6C; &#xBAA9;&#xC801;.

&#xD575; &#xC804; &#xC81C;&#xC774;&#xCF65;&#xC758; hippocampal &#xB274;&#xB7F0;&#xC5D0;&#xC11C; &#xC790;&#xADF9; &#xC7A5;&#xAE30; potentiation &#xD558;&#xC9C0;&#xB9CC; &#xD558;&#xC9C0; &#xC7A5;&#xAE30; &#xBD88;&#xD669;&#xC744; &#xC720;&#xB3C4; &#xD55C; &#xD6C4;.

En los &uacute;ltimos a&ntilde;os se ha caracterizado una serie de posibles mensajeros de la prote&iacute;na nuclear synapto que se cree que son involucrados en la expresi&oacute;n de genes relacionados con la plasticidad y tienen la capacidad de importin - mediada y dependientes de actividad nuclear de importaci&oacute;n. Sin embargo, hay una sorprendente falta de datos que muestran la importaci&oacute;n nuclear de tales prote&iacute;nas en modelos celulares del aprendizaje y la memoria. S&oacute;lo recientemente se encontr&oacute; que la transcripci&oacute;n factor AMP c&iacute;clico respuesta elemento prote&iacute;na 2 (CREB2) transita al n&uacute;cleo durante la depresi&oacute;n a largo plazo (LTD), pero no durante la potenciaci&oacute;n a largo plazo (LTP) de la transmisi&oacute;n sin&aacute;ptica en neuronas hipocampales de primarias. Jacob es otro mensajero que parejas la actividad del receptor de NMDA a la expresi&oacute;n de genes nucleares. Por lo tanto decidimos estudiar si Jacob se acumula en el n&uacute;cleo en modelos fisiol&oacute;gicos relevantes de plasticidad sin&aacute;ptica dependiente de la actividad.

Translocaci&oacute;n nuclear de jacob en neuronas de hipocampales tras est&iacute;mulos induciendo potenciaci&oacute;n a largo plazo pero no a largo plazo depresi&oacute;n.

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity.

MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity.

Activity-dependent synaptic plasticity is associated with synaptic protein turnover involving the ubiquitin proteasome system (UPS) for protein degradation. In primary hippocampal cell culture, it has been shown that increased or decreased activity of synaptic transmission can regulate the amount of postsynaptic density (PSD) proteins via UPS. However, the specific spatio-temporal dynamic of PSD protein degradation after LTP induction and its downstream signaling pathways remains to be clarify. We used confocal microscopy to monitor levels of eGFP-tagged SPAR (spine-associated Rap GTPase activating protein) expressed in acute hippocampal slices and found that LTP induction triggered a UPS-dependent decay of eGFP-SPAR fluorescence. SPAR degradation was reduced upon inhibition of cyclin-dependent kinase 5 (CDK5) as well as by a protein synthesis inhibitor. Comparison of eGFP-tagged SPAR levels with those obtained in control experiments with eGFP revealed a protein synthesis-independent component of LTP-associated SPAR degradation. This second component required UPS and NMDA receptor activation but not CDK5. We conclude that LTP triggers a down regulation of SPAR by two complementary mechanisms, one of which has previously been described to mediate homeostatic plasticity.

Hippocampal LTP triggers proteasome-mediated SPAR degradation in CA1 neurons.

Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25 μM) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1 μM) and sulpiride (1 and 40 μM). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10 μM). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25 μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors.

MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors.

Epidemiological and clinico-pathological studies indicate a causal relationship between heart disease and Alzheimer's disease (AD). To learn whether heart disease causes an onset of AD, mice with myocardial infarction (MI) and congestive heart failure (HF) were used to test neuropsychiatric and cognitive behaviors as well as for measurements of AD related protein markers. To this end, adult mice were subjected to ligation of left anterior descending artery (LAD) and about two weeks later high-frequency echocardiography was performed to exam the resulting cardiac structure and function. Three months after successful induction of chronic heart failure (CHF) these mice showed an impairment of learning in the Morris Water Maze task. In addition, the expression of selected molecules, which are involved in β-amyloid metabolism, apoptosis and inflammation on the level of gene transcription and translation, was altered in CHF mice. Our findings provide a plausible explanation that CHF increases the risk of cognitive impairments and alters cerebral β-amyloid metabolism. In addition, our data indicate that the cerebral compensatory mechanisms in response to CHF are brain area and gender specific.

Increases in the risk of cognitive impairment and alterations of cerebral β-amyloid metabolism in mouse model of heart failure.

γ-Secretase plays an important role in the generation of amyloid beta and the activation of Notch receptors. In the hope that the reduction of amyloid production can help to battle Alzheimer's disease (AD) secretases were suggested to represent a potential therapeutic targets. However, the role of γ-secretase in cellular mechanisms of memory formation under physiological conditions remained to be clarified. To this end, γ-secretase was inhibited by bath-application of DAPT or Compound E and the effects on activity-dependent hippocampal synaptic plasticity and basal synaptic transmission in acute hippocampal slices from Wistar rats were examined. Bath application of DAPT or Compound E over the whole recording period of field excitatory postsynaptic potential (fEPSP) caused a reduction of synaptic potentiation within 1h after 3×1s 100Hz/10min stimulation (HFS) of Schaffer-collateral CA1 synapses. Notably, DAPT and Compound E inhibited effectively long-term potentiation (LTP) of fEPSPs when it was applied after HFS, but not if applied only during the tetanization paradigm. Compounds did not affect basal synaptic transmission, paired-pulse facilitation and NMDA mediated fEPSPs. Our data thus imply that γ-secretase plays a role in LTP and most notably for the persistence of activity dependent synaptic plasticity, presumably through the reduction of endogenous amyloid beta and/or Notch receptor activation. Targeting of γ-secretase to prevent the onset of AD might by itself alter memory formation.

The role of γ-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a severe decline of memory performance. A widely studied AD mouse model is the APPswe/PSEN1ΔE9 (APP/PS1) strain, as mice exhibit amyloid plaques as well as impaired memory capacities. To test whether restoring synaptic plasticity and decreasing β-amyloid load by Parkin could represent a potential therapeutic target for AD, we crossed APP/PS1 transgenic mice with transgenic mice overexpressing the ubiquitin ligase Parkin and analyzed offspring properties. Overexpression of Parkin in APP/PS1 transgenic mice restored activity-dependent synaptic plasticity and rescued behavioral abnormalities. Moreover, overexpression of Parkin was associated with down-regulation of APP protein expression, decreased β-amyloid load and reduced inflammation. Our data suggest that Parkin could be a promising target for AD therapy.

Parkin overexpression ameliorates hippocampal long-term potentiation and β-amyloid load in an Alzheimer's disease mouse model.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease-like symptoms following administration to mice, monkeys, and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP(+)) to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra (SN). Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, SN and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP(+). Here, we present data showing that acute bath-application of MPP(+) elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP(+) were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters did not prevent but increased the depression of excitatory post-synaptic field potentials. In the search for a possible mechanism, we observed that MPP(+) reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory post-synaptic currents. The acute effect of MPP(+) on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP(+) affects hippocampal synaptic transmission by enhancing some aspects of the hippocampal GABAergic system.

The neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system.

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons.

While the brain-derived neurotrophic factor (BDNF) gene and its multiple transcripts have been recognized as a key factor for learning, but the specific involvement of BDNF translated from BDNF transcripts with short-3' untranslated region (short 3' UTR) in learning and memory requires further analysis. In this paper, we present data to show that the transduction of hippocampal CA1 neurons with AAV9-5' UTR-BDNF (short 3' UTR)-IRES-ZsGreen and the subsequent expression of BDNF enhanced the phosphorylation of synaptic plasticity relevant proteins and improved passive avoidance and object location, but not object recognition memory. In addition, BDNF improved the relearning of object location. At higher BDNF overexpression levels, the fear behavior was accompanied with a decline in the passive avoidance memory 24h post training, and with an enhanced fear conditioning performance. In addition, these animals developed spontaneous seizures. Thus, the expression of BDNF in the hippocampal CA1 region has the potential to improve fear and object location memory in wild type mouse strains when the region and expression levels of BDNF are well controlled.

Translation of BDNF-gene transcripts with short 3' UTR in hippocampal CA1 neurons improves memory formation and enhances synaptic plasticity-relevant signaling pathways.

The elongation factor 2 kinase (eEF2K), likewise known as CaMKIII, has been demonstrated to be involved in antidepressant responses of NMDA receptor antagonists. Even so, it remains open whether direct inhibition of eEF2K without altering up-stream or other signaling pathways affects hippocampal synaptic transmission and neuronal network synchrony. Inhibition of eEF2K by the selective and potent eEF2K inhibitor A-484954 induced a fast pre-synaptically mediated enhancement of synaptic transmission and synchronization of neural network activity. The eEF2K-inhibition mediated potentiation of synaptic transmission of hippocampal CA1 neurons is most notably independent of protein synthesis and does not rely on protein kinase C, protein kinase A or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1/2. Moreover, the strengthening of synaptic transmission in the response to the inhibition of eEF2K was strongly attenuated by the inhibition of p38 MAPK. In addition, we show the involvement of barium-sensitive and more specific the TWIK-related potassium-1 (TREK-1) channels in the eEF2K-inhibition mediated potentiation of synaptic transmission. These findings reveal a novel pathway of eEF2K mediated regulation of hippocampal synaptic transmission. Further research is required to study whether such compounds could be beneficial for the development of mood disorder treatments with a fast-acting antidepressant response.

Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms.

The hippocampal area Cornu Ammonis (CA) CA2 is important for social interaction and is innervated by Substance P (SP)-expressing supramammillary (SuM) nucleus neurons. SP exerts neuromodulatory effects on pain processing and central synaptic transmission. Here we provide evidence that SP can induce a slowly developing NMDA receptor- and protein synthesis-dependent potentiation of synaptic transmission that can be induced not only at entorhinal cortical (EC)-CA2 synapses but also at long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. In addition, SP-induced potentiation of SC-CA2 synapses transforms a short-term potentiation of EC-CA2 synaptic transmission into LTP, consistent with the synaptic tagging and capture hypothesis. Interestingly, this SP-induced potentiation and associative interaction between the EC and SC inputs of CA2 neurons is independent of the GABAergic system. In addition, CaMKIV and PKMζ play a critical role in the SP-induced effects on SC-CA2 and EC-CA2 synapses. Thus, afferents from SuM neurons are ideally situated to prime CA2 synapses for the formation of long-lasting plasticity and associativity.

Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2.

Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening.

Article	Year
Nuclear translocation of jacob in hippocampal neurons after stimuli inducing long-term potentiation but not long-term depression. PloS one\| PubMed ID: 21364755	2011
MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity. Toxicology and applied pharmacology\| PubMed ID: 21605582	2011
Hippocampal LTP triggers proteasome-mediated SPAR degradation in CA1 neurons. Synapse (New York, N.Y.)\| PubMed ID: 21987493	2012
MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors. Journal of neurochemistry\| PubMed ID: 22651101	2012
Increases in the risk of cognitive impairment and alterations of cerebral β-amyloid metabolism in mouse model of heart failure. PloS one\| PubMed ID: 23737953	2013
The role of γ-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity. Neuroscience letters\| PubMed ID: 24016412	2013
Parkin overexpression ameliorates hippocampal long-term potentiation and β-amyloid load in an Alzheimer's disease mouse model. Human molecular genetics\| PubMed ID: 24105468	2014
The neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system. Frontiers in cellular neuroscience\| PubMed ID: 26300734	2015
Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons. Journal of Alzheimer's disease : JAD\| PubMed ID: 26890755	2016
Translation of BDNF-gene transcripts with short 3' UTR in hippocampal CA1 neurons improves memory formation and enhances synaptic plasticity-relevant signaling pathways. Neurobiology of learning and memory\| PubMed ID: 27394686	2017
Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms. Frontiers in cellular neuroscience\| PubMed ID: 27826228	2016
Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 28973908	2017
Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4-receptors in the CA1 area of hippocampus. Scientific reports\| PubMed ID: 29138490	2017

Thomas Behnisch

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