RESUMO
Space radiation, including high-mass, high-Z, high-energy particles (HZE; e.g. (56)Fe), represents a significant health risk for astronauts, and the central nervous system (CNS) may be a vulnerable target. HZE-particle radiation may directly affect neuronal function, or during immunological challenge, it may alter immune system-to-CNS communication. To test these hypotheses, we exposed mice to accelerated iron particles ((56)Fe; 600 MeV/nucleon; 1, 2, 4 Gy; brain only) and 1 month later prepared hippocampal slices to measure the effects of radiation on neurotransmission and synaptic plasticity in CA1 neurons. In a model of immune system-to-CNS communication, these electrophysiological parameters were measured in irradiated mice additionally challenged with the peripheral immunological stressor lipopolysaccharide (LPS) injected intraperitoneally 4 h before the slice preparation. Exposure to (56)Fe particles alone increased dendritic excitability and inhibited plasticity. In control mice (0 Gy), LPS treatment also inhibited synaptic plasticity. Paradoxically, in mice exposed to 2 Gy, the LPS treatment restored synaptic plasticity to levels similar to those found in controls (0 Gy, no LPS). Our results indicate that HZE-particle radiation alters normal electrophysiological properties of the CNS and the hippocampal response to LPS.
Assuntos
Radiação Cósmica , Hipocampo/efeitos da radiação , Lipopolissacarídeos/farmacologia , Plasticidade Neuronal/efeitos da radiação , Sinapses/efeitos da radiação , Animais , Ferro/farmacologia , Potenciação de Longa Duração/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Cortistatin-14 (CST) is a neuropeptide expressed in cortical and hippocampal interneurons that shares 11 of 14 residues with somatostatin. In contrast to somatostatin, infusion of CST decreases locomotor activity and selectively enhances slow wave sleep. Here, we show that transgenic mice that overexpress cortistatin under the control of neuron-specific enolase promoter do not express long-term potentiation in the dentate gyrus. This blockade of dentate LTP correlates with profound impairment of hippocampal-dependent spatial learning. Exogenously applied CST to slices of wild-type mice also blocked induction of LTP in the dentate gyrus. Our findings implicate cortistatin in the modulation of synaptic plasticity and cognitive function. Thus, increases in hippocampal cortistatin expression during aging could have an impact on age-related cognitive deficits.
Assuntos
Hipocampo/metabolismo , Deficiências da Aprendizagem/genética , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Peptídeos/metabolismo , Transmissão Sináptica/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Peptídeos e Proteínas de Sinalização Intercelular , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Peptídeos/genética , Regiões Promotoras Genéticas/genéticaRESUMO
The selective loss of somatostatin (SST)-containing interneurons from the hilus of the dentate gyrus is a hallmark of epileptic hippocampus. The functional consequence of this loss, including its contribution to postseizure hyperexcitability, remains unclear. We address this issue by characterizing the actions of SST in mouse dentate gyrus using electrophysiological techniques. Although the majority of dentate SST receptors are located in the outer molecular layer adjacent to lateral perforant path (LPP) synapses, we found no consistent action of SST on standard synaptic responses generated at these synapses. However, when SST was present during application of high-frequency trains that normally generate long-term potentiation (LTP), the induction of LTP was impaired. SST did not alter the maintenance of LTP when applied after its induction. To examine the mechanism by which SST inhibits LTP, we recorded from dentate granule cells and examined the actions of this neuropeptide on synaptic transmission and postsynaptic currents. Unlike findings in the CA1 hippocampus, we observed no postsynaptic actions on K(+) currents. Instead, SST inhibited Ca(2+)/Ba(2+) spikes evoked by depolarization. This inhibition was dependent on N-type Ca(2+)currents. Blocking these currents also blocked LTP, suggesting a mechanism through which SST may inhibit LTP. Our results indicate that SST reduction of dendritic Ca(2+) through N-type Ca(2+) channels may contribute to modulation of synaptic plasticity at LPP synapses. Therefore the loss of SST function postseizure could result in abnormal synaptic potentiation that contributes to epileptogenesis.