Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Multimodal astrocyte–neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4–7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8–10. However, the existence of this mechanism has been questioned11–13 owing to inconsistent data14–17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18–21 and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging22 in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target

Neuregulin 1 signalling modulates mGluR1 function in mesencephalic dopaminergic neurons.

Neuregulin 1 (NRG1) is a trophic factor that has an essential role in the nervous system by modulating neurodevelopment, neurotransmission and synaptic plasticity. Despite the evidence that NRG1 and its receptors, ErbB tyrosine kinases, are expressed in mesencephalic dopaminergic nuclei and their functional alterations are reported in schizophrenia and Parkinson’s disease, the role of NRG1/ErbB signalling in dopaminergic neurons remains unclear. Here we found that NRG1 selectively increases the metabotropic glutamate receptor 1 (mGluR1)-activated currents by inducing synthesis and trafficking to membrane of functional receptors and stimulates phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which is required for mGluR1 function. Notably, an endogenous NRG1/ErbB tone is necessary to maintain mGluR1 function, by preserving its surface membrane expression in dopaminergic neurons. Consequently, it enables striatal mGluR1-induced dopamine outflow in in vivo conditions. Our results identify a novel role of NRG1 in the dopaminergic neurons, whose functional alteration might contribute to devastating diseases, such as schizophrenia and Parkinson’s disease

Estudio detallado de suelo de la Finca Inversiones Flor cola S. de R.L. Checa, Pichincha, Ecuador

49 p.Tipán, Moshe. 2006. Estudio detallado de suelo de la Finca Inversiones Flor cola S. de R.L. Checa, Pichincha, Ecuador. Proyecto Especial del Programa de Ingeniero Agr nomo, Zamorano, Honduras. 49 p. La actividad flor cola en Ecuador se estableci en los a os 90, dadas las condiciones clim ticas y de ubicaci n favorable para la producci n de flores de alta calidad; queda como factor cr tico, el manejo del suelo para alcanzar productividades altas en forma competitiva y amigable al ambiente. El objetivo fue elaborar el estudio detallado de las propiedades morfol gicas, f sicas y qu micas del suelo con en el fin de emitir recomendaciones para su manejo en la Finca Inversiones Flor cola S. de R.L., Checa, Ecuador del grupo DOLE. Se determinaron en perfiles de suelo las caracter sticas morfol gicas, f sicas y qu micas. Con las caracter sticas f sicas y morfol gicas se clasificaron los suelos y se elaboraron mapas de la condici n actual y potencial del suelo, se identificaron las limitantes y se emitieron planes para alcanzar la mejor condici n. Se implementaron ndices de calidad de suelo para cuantificar el condici n actual y potencial del suelo. Se encontraron limitantes como: horizontes compactados entre los 40 y 80 cm de profundidad, horizonte cementado (Cm) presente entre los 43 y 80 cm, extremadamente firme, con resistencia a la penetraci n mayor a 4.5 kg/cm2 que dificulta el drenaje. La profundidad efectiva del suelo es muy superficial en el 83.7% de los casos ya que se encuentra en los primeros 40 cm, los colores pardo gris ceo muy oscuro y pardo muy oscuro indican contenidos medios de materia org nica en la superficie, en los horizontes profundos indican drenaje interno pobre ocasional. Las texturas predominantes son: franca arenosa, franca arenosa gruesa, fina, franca y arena franca, la estructura en los primeros 30 cm es granular fina y media, entre los 30 y 80 cm son bloques subangulares gruesos y muy gruesos, d biles, firmes y muy firmes, con poros pocos, medianos y gruesos. La frecuencia y el tama o de ra ces disminuyen en los horizontes Ad y Cm. Se observan problemas de antagonismos entre cationes y disponibilidad limitada de nutrientes por pH. En conclusi n, el 83.7% de los suelos de la finca son de aptitud clase IV y 61.2% tiene potencial clase II. El ndice actual del suelo puede ser mejorado en un 34.3% de la finca, con manejo enfocado a mecanizaci n, elaboraci n de camas, mejores pr cticas de riego, adici n de materia org nica, fertilizaci n, drenaje y reordenamiento de cultivos.1. Índice de cuadros 2. Índice de figuras 3. Índice de anexos 4. Introducción 5. Materiales y métodos 6. Resultados y discusión 7. Conclusiones 8. Recomendaciones 9. Literatura citada 10. Anexo

Neuregulin 1/ErbB signalling modulates hippocampal mGluRI-dependent LTD and object recognition memory

The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRI)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRI-induced glutamatergic long-term depression (mGluRI-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRI-LTD has never been considered. Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRI-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRI in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRI agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRI-dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRI. We found that NRG1 potentiates mGluRI-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRI, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRI-induced neuronal excitation and mGluRI-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRI-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test. Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRI-dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases

Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer's Disease

What happens precociously to the brain destined to develop Alzheimer's Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing. Here, we deeply investigate the physiology of DA neurons in the VTA before, at the onset, and after onset of VTA neurodegeneration. We use the Tg2576 mouse model of AD, overexpressing a mutated form of the human APP, to identify molecular targets that can be manipulated pharmacologically. We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology. Importantly, these changes are associated with accumulation of autophagosomes, suggestive of a dysfunctional autophagy, and with enhanced activation of c-Abl, a tyrosine kinase previously implicated in the pathogenesis of neurodegenerative diseases. Chronic treatment of Tg2576 mice with Nilotinib, a validated c-Abl inhibitor, reduces c-Abl phosphorylation, improves autophagy, reduces A\u3b2 levels and - more importantly - prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA. Interestingly, the drug prevents the reduction of DA outflow to the hippocampus and ameliorates hippocampal-related cognitive functions. Our results strive to identify early pathological brain changes in AD, to provide a rational basis for new therapeutic interventions able to slow down the disease progression

Modular organization of the brainstem noradrenaline system coordinates opposing learning states

International audienceNoradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility