RESUMO
Experience-dependent synapse refinement is essential for functional optimization of neural circuits. However, how sensory experience sculpts excitatory synaptic transmission is poorly understood. Here, we show that despite substantial remodeling of synaptic connectivity, AMPAR-mediated synaptic transmission remains at equilibrium during the critical period in the mouse primary visual cortex. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity. With normal visual experience, loss of Ng decreased AMPAR-positive synapse numbers, prevented AMPAR-silent synapse maturation, and increased spine elimination. Importantly, visual deprivation halted synapse loss caused by loss of Ng, revealing that Ng coordinates experience-dependent AMPAR-silent synapse conversion to AMPAR-active synapses and synapse elimination. Loss of Ng also led to sensitized long-term synaptic depression (LTD) and impaired visually guided behavior. Our synaptic interrogation reveals that experience-dependent coordination of AMPAR-silent synapse conversion and synapse elimination hinges upon Ng-dependent mechanisms for constructive synaptic refinement during the critical period.
Assuntos
Receptores de AMPA/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Técnicas In Vitro , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogranina/antagonistas & inibidores , Neurogranina/genética , Neurogranina/metabolismo , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Córtex Visual/metabolismoRESUMO
Neurogranin has been suggested to serve as a common regulator synchronizing the activities of PKC and CaMKII in acute opioid tolerance. To examine if a similar mechanism exists in acute opioid dependence, we directly targeted neurogranin using antisense oligodeoxynucleotides. Male ICR mice were pretreated with neurogranin antisense or mismatch oligodeoxynucleotides (2 microg/day, i.c.v.) for 3 consecutive days. On Day 4, morphine (100 mg/kg, s.c.) was used to induce dependence, as revealed by naloxone-precipitated withdrawal in saline or mismatch-pretreated mice. Antisense-pretreated mice showed decreased neurogranin expression, lack of morphine-induced phosphorylation of neurogranin and activation of CaMKII and CREB, and absence of naloxone-induced withdrawal jumping. Taken together, these data suggest that neurogranin plays an essential role in acute opioid dependence, possibly by affecting the CaMKII and CREB signaling pathway.