RESUMO
Complexins (Cplxs) are key regulators of synaptic exocytosis, but whether they act as facilitators or inhibitors is currently being disputed controversially. We show that genetic deletion of all Cplxs expressed in the mouse brain causes a reduction in Ca(2+)-triggered and spontaneous neurotransmitter release at both excitatory and inhibitory synapses. Our results demonstrate that at mammalian central nervous system synapses, Cplxs facilitate neurotransmitter release and do not simply act as inhibitory clamps of the synaptic vesicle fusion machinery.
Assuntos
Cálcio/metabolismo , Exocitose , Proteínas do Olho/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neurotransmissores/metabolismo , Sinapses/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Cálcio/farmacologia , Potenciais Evocados , Exocitose/genética , Proteínas do Olho/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/fisiologia , Transmissão Sináptica , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismoRESUMO
BACKGROUND: Erythropoietin (EPO) improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity. RESULTS: We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP), a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses. CONCLUSION: We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.
Assuntos
Eritropoetina/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Células Cultivadas , Eletrofisiologia , Hipocampo/fisiologia , Immunoblotting , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Camundongos , Microscopia Confocal , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/fisiologiaRESUMO
This study was aimed to characterize the earliest phases of synapse development in mouse retinal ganglion cells (RGCs) by recording spontaneous postsynaptic currents (PSCs). First PSCs were detected at embryonic day 17 and completely suppressed by bicuculline, demonstrating their GABAergic nature. Starting from postnatal day 3 a small fraction of RGCs had rapidly decaying, most likely glutamatergic currents. The present results suggest that functional GABAergic synapses with RGCs appear before birth and that GABAergic synaptic transmission precedes that of glutamate in the retina. In this early period GABA acts in a depolarizing manner and takes over an excitatory function.