RESUMO
The opioid system influences learning and memory processes. However, neural mechanisms underlying the modulation of hippocampal activity by opioid receptors remain largely unknown. Here, we compared how mu and delta receptors operate within the mouse CA1 network, and used knock-in mice expressing functional delta opioid receptors fused to the green fluorescent protein (DOR-eGFP) to determine how delta opioid receptor-expressing interneurons integrate within the hippocampal circuitry. Through whole cell patch-clamp recording of CA1 pyramidal neurons from wild-type and DOR-eGFP mice, we found that mu and delta receptors both modulate spontaneous GABAergic inhibition received by these cells. Interestingly, mu but not delta receptor activation decreased the feed-forward inhibitory input evoked by Schaffer collateral stimulation. However, mu and delta agonists modulated GABAergic feed-forward inhibition when evoked upon stimulation of the temporoammonic pathway. In addition, anterograde tracing using biotinylated dextran amine injected into the entorhinal cortex of DOR-eGFP mice suggests the existence of synaptic contacts between temporoammonic afferents and delta receptor-expressing interneurons processes in CA1. Altogether, our data demonstrate a distinct modulatory role of the hippocampal network activity by mu and delta opioid receptors, and show for the first time that delta receptor-expressing interneurons in the CA1 are recruited by the temporoammonic pathway rather than the Schaffer collateral.
Assuntos
Região CA1 Hipocampal/metabolismo , Potenciais Evocados/fisiologia , Neurônios GABAérgicos/metabolismo , Células Piramidais/metabolismo , Receptores Opioides delta/metabolismo , Animais , Região CA1 Hipocampal/citologia , Neurônios GABAérgicos/citologia , Camundongos , Camundongos Transgênicos , Células Piramidais/citologia , Receptores Opioides delta/genéticaRESUMO
Pharmacological data suggest that delta opioid receptors modulate learning and memory processes. In the present study, we investigated whether inactivation of the delta opioid receptor modifies hippocampus (HPC)- and striatum-dependent behaviors. We first assessed HPC-dependent learning in mice lacking the receptor (Oprd1(-/-) mice) or wild-type (WT) mice treated with the delta opioid antagonist naltrindole using novel object recognition, and a dual-solution cross-maze task. Second, we subjected mutant animals to memory tests addressing striatum-dependent learning using a single-solution response cross-maze task and a motor skill-learning task. Genetic and pharmacological inactivation of delta opioid receptors reduced performance in HPC-dependent object place recognition. Place learning was also altered in Oprd1(-/-) animals, whereas striatum-dependent response and procedural learning were facilitated. Third, we investigated the expression levels for a large set of genes involved in neurotransmission in both HPC and striatum of Oprd1(-/-) mice. Gene expression was modified for several key genes that may contribute to alter hippocampal and striatal functions, and bias striatal output towards striatonigral activity. To test this hypothesis, we finally examined locomotor effects of dopamine receptor agonists. We found that Oprd1(-/-) and naltrindole-treated WT mice were more sensitive to the stimulant locomotor effect of SKF-81297 (D1/D5), supporting the hypothesis of facilitated striatonigral output. These data suggest, for the first time, that delta receptor activity tonically inhibits striatal function, and demonstrate that delta opioid receptors modulate learning and memory performance by regulating the HPC/striatum balance.
Assuntos
Corpo Estriado/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Atividade Motora/fisiologia , Destreza Motora/fisiologia , Receptores Opioides delta/deficiência , Animais , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Opioides delta/genéticaRESUMO
Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role on hippocampal activity. We used fluorescent knock-in mice that express a functional delta opioid receptor fused at its carboxy terminus with the green fluorescent protein in place of the native receptor to investigate the receptor neuroanatomical distribution in this structure. Fine mapping of the pyramidal layer was performed in hippocampal acute brain slices and organotypic cultures using fluorescence confocal imaging, co-localization with pre- and postsynaptic markers and correlative light-electron microscopy. The different approaches concurred to identify delta opioid receptors on presynaptic afferents to glutamatergic principal cells. In the latter, only scarce receptors were detected that were confined within the Golgi or vesicular intracellular compartments with no receptor present at the cell surface. In the mouse hippocampus, expression of functional delta opioid receptors is therefore mostly associated with interneurons emphasizing a presynaptic modulatory effect on the pyramidal cell firing rate.
Assuntos
Hipocampo/metabolismo , Terminações Pré-Sinápticas/metabolismo , Células Piramidais/metabolismo , Receptores Opioides delta/metabolismo , Vias Aferentes/citologia , Vias Aferentes/metabolismo , Animais , Feminino , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Técnicas de Cultura de Órgãos , Dor/metabolismo , Dor/patologia , Células Piramidais/citologia , Receptores Opioides delta/genéticaRESUMO
BACKGROUND: Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene mutations are associated with cognitive impairment ranging from nonsyndromic X-linked mental retardation to autism. IL1RAPL1 belongs to a novel family of Toll/IL-1 receptors, whose expression in the brain is upregulated by neuronal activity. Currently, very little is known about the function of this protein. We previously showed that IL1RAPL1 interacts with the neuronal calcium sensor NCS-1 and that it regulates voltage-gated calcium channel activity in PC12 cells. RESULTS: Here we show that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major component of excitatory postsynaptic compartment. Using gain- and loss-of-function experiments in neurons, we demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling c-Jun terminal kinase (JNK) activity and PSD-95 phosphorylation. Mice carrying a null mutation of the mouse Il1rapl1 gene show a reduction of both dendritic spine density and excitatory synapses in the CA1 region of the hippocampus. These structural abnormalities are associated with specific deficits in hippocampal long-term synaptic plasticity. CONCLUSION: The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism of cognitive impairment associated with alterations of the JNK pathway leading to a mislocalization of PSD-95 and abnormal synaptic organization and function.