Comunicación sinapsis-núceo 2.pdf
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Segunda Parte: El camino de vuelta Del núcleo a la sinapsis Del núcleo a la sinapsis Cómo llegan las macromoléculas a las sinapsis específicas? a las sinapsis específicas? Hipótesis para explicar la especificidad sináptica Synaptic Tagging New gene products or proteins New gene products or products or proteins Synaptic tag NMDAR Signal to nucleus Synaptic Potentiation Locally generated tag captures new gene product d t Synaptic tagging Frey y Morris Haydée Viola Ejemplos de síntesis local en plasticidad neuronal: Ejemplos de síntesis local en plasticidad neuronal: ‐Facilitación por 5‐HT en Aplysia ‐Síntesis de Activity‐regulated y g cytoskeleton y asociated p p. (Arc) ( ) ‐ Síntesis de CaMKII ‐Síntesis de PKMz Síntesis proteica local Martin et al., al Cell 91:927 91:927-38 38 (1997) Sistema de neurona sensorial bifurcada Facilitación sinápsisespecífica de corto y g término largo LTF sinapsis‐especifica requiere de transcripción LTF requiere síntesis proteica local en la pre‐sinapsis Captura sináptica Mecanismos de regulación traduccional: g ‐ Activación de eIFs ‐Poliadenilación – CPEB ‐FRMP Regulación traduccional CaMKIIalfa mRNA Mecanismos de transporte de mRNAs: A través de unión de mRNA BP a secuencias 3´ UTR ‐Zip codes sequences ZBP: actina ‐CPE – CPEB: CaMKII Seminario ‐FMRP – FMRP Staufen St f (sería un mecanismo de captura de mRNA a las sinapsis) Transporte anterógrado SEGUNDA PARTE El camino de vuelta Del núcleo a la sinápsis Localización de mRNA y proteina en las sinápsis activadas Steward et al, Neuron 21:741‐51 (1998) Localización en el tiempo de Arc mRNA Localización en el tiempo de Arc Steward and Worley, PNAS 2001 Localización de la proteína Arc Steward et al, Neuron 21:741‐51 (1998) ¿Qué papel cumple Arc en las espinas dendríticas? LTD LTP Papel de PKMz en el mantenimiento del LTP y la memoria Domain Structures of Isoforms of PKC Regulatory Domain Catalytic Domain Classical alpha Beta Gamma PS Phospholipid •• Calcium ATP •• Novel Delta Epsilon Eta Theta Mu Atypical yp Lambda/Iota Zeta Hinge Region Substrate •• Auto‐ Auto phosphorylation sites PKM mRNA Formation from Internal Promoter within PKC Gene within PKC Gene PKM and LTP Maintenance ZIP: PKMz pseudosubstrate inhibitory peptide Figure 1. Effect of ZIP on very long‐term CTA memory in the insular cortex. (A) ZIP/vehicle were administered 3 mo after training, and memory was tested 2 d later. The dashed line indicates equal preference for the CS and water, i.e., AI = 50. (B) ZIP/vehicle/scrambled ZIP were administered 1 mo after training, and memory was tested 12 d later. Saccharin was the d i i t d1 ft t i i d t t d 12 d l t S h i th CS in both A and B. Shema et al., Learning & Memory 2009 ZIP abolishes very long‐term memory The effect of ZIP is long lasting even when the inhibitor is applied long after encoding Intensive training and robust memory do not Intensive training and robust memory do not confer immunity to ZIP effect Once erased and reacquired, CTA can be erased again by ZIP ZIP is ineffective during conditioning and immediately afterward La inyección de PKMz aumenta más de una memoria El KO de PKMz tiene aprendizaje y memoria normal Prkcz null mice show normal learning and memory Anna M. Lee et al Nature. 2013 January 17; 493(7432): 416–419 Figure 3. Intact learning and memory in Prkcz g g y −/− mice a, In cued fear conditioning, wild‐type (n=20) and Prkcz / , g, yp ( ) −/− mice (n=27) / ( ) showed similar levels of freezing during all three sessions. b, During the novel object task, Prkcz −/− (n=17) and wild‐type mice (n=16) spent more time exploring the new object compared with the old object. There was no genotype difference in exploration of old or novel object. c, In the spatial memory task, Prkcz −/− (n=13) and wild‐type mice (n=12) spent more time exploring the new location compared with the old location and there was no genotype difference in exploration of either location. d, Prkcz −/− (n=11) and wild type mice (n=12) remained on the accelerating rotarod for similar amounts of time and showed similar (n=11) and wild‐type mice (n=12) remained on the accelerating rotarod for similar amounts of time and showed similar improvement in this task over successive trials. e, In the conditioned place preference test, Prkcz −/− (n=7) and wild‐type mice (n=8) showed similar preference for the cocaine‐paired chamber when tested one day after the last conditioning session. f, Compared with injection of saline (n=9), injection of ZIP (n=13) into the Nac ignificantly reduced expression of cocaine CPP in Prkcz −/− mice. All data is shown as mean ± s.e.m.
