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1.
Neurobiol Learn Mem ; 114: 101-112, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24882624

RESUMEN

Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Memoria/fisiología , Plasticidad Neuronal/fisiología , Terminales Presinápticos/metabolismo , Sinapsis/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Miedo/fisiología , Proteínas de Unión al GTP/metabolismo , Hipocampo/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Proteínas/farmacología , Sinapsis/efectos de los fármacos , Proteína 25 Asociada a Sinaptosomas/metabolismo
2.
PLoS Comput Biol ; 7(6): e1002084, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21738458

RESUMEN

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.


Asunto(s)
Adenilil Ciclasas/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Potenciación a Largo Plazo/fisiología , Células Piramidales/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Calcio/metabolismo , Colforsina/farmacología , Simulación por Computador , AMP Cíclico/metabolismo , Difusión , Dopamina/metabolismo , Ratones , Modelos Biológicos , Proteínas/farmacología , Células Piramidales/fisiología , Procesos Estocásticos , Especificidad por Sustrato , Potenciales Sinápticos/efectos de los fármacos
3.
Front Behav Neurosci ; 16: 1091082, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36699657

RESUMEN

Modifying established behavior in novel situations is essential, and patients with neuropsychiatric disorders often lack this flexibility. Understanding how novelty affects behavioral flexibility therefore has therapeutic potential. Here, novelty differentially impacts connectivity within the ventral tegmental-hippocampal-medial prefrontal (VTA-HPC-mPFC) circuit, thereby enhancing the ability of mice to overcome established behavioral bias and adapt to new rules. Circuit connectivity was measured by local field potential (LFP) coherence. As mice exposed to novelty learned to overcome previously established spatial bias, the ventral HPC (vHPC) strengthens its coherence with the VTA and mPFC in theta frequency (4-8 Hz). Novelty or learning did not affect circuits involving the dorsal HPC (dHPC). Without novelty, however, mice continued following established spatial bias and connectivity strength remained stable in the VTA-HPC-mPFC circuit. Pharmacologically blocking dopamine D1-receptors (D1Rs) in the vHPC abolished the behavioral and physiological impacts of novelty. Thus, novelty promotes behavioral adaptation by permitting learning-associated plasticity in the vHPC-mPFC and VTA-vHPC circuit, a process mediated by D1Rs in the vHPC.

4.
Mol Brain ; 13(1): 145, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-33172471

RESUMEN

Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, translin knockout (KO) mice, which lack translin/trax, exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome (fragile X mental retardation protein-FMRP-KO mice). Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic protein kinase A (PKA) activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression (mGluR-LTD), a hallmark of the FMRP KO mice. On the contrary, translin KO mice exhibited deficits in N-methyl-D-aspartate receptor (NMDAR) dependent LTD, a phenotype not observed in the FMRP knockouts. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling and suggest that translin/trax and FMRP play distinct roles in hippocampal synaptic plasticity.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Hipocampo/fisiología , Plasticidad Neuronal , Proteínas de Unión al ARN/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Potenciación a Largo Plazo/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Elife ; 62017 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-28927503

RESUMEN

Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at activated synapses. We find that mice lacking translin/trax display defects in synaptic tagging, which requires protein synthesis at activated synapses, and long-term memory. Hippocampal samples harvested from these mice following learning show increases in several disease-related microRNAs targeting the activin A receptor type 1C (ACVR1C), a component of the transforming growth factor-ß receptor superfamily. Furthermore, the absence of translin/trax abolishes synaptic upregulation of ACVR1C protein after learning. Finally, synaptic tagging and long-term memory deficits in mice lacking translin/trax are mimicked by ACVR1C inhibition. Thus, we define a new memory mechanism by which learning reverses microRNA-mediated silencing of the novel plasticity protein ACVR1C via translin/trax.


Asunto(s)
Receptores de Activinas Tipo I/metabolismo , Proteínas de Unión al ADN/metabolismo , Expresión Génica , Aprendizaje , Memoria , Proteínas de Unión al ARN/metabolismo , Ribonucleasas/metabolismo , Animales , Hipocampo/fisiología , Ratones , Plasticidad Neuronal
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