Plasticidad sináptica en el hipocampo regulada por factores endocrinos. Papel de la prolactina

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Anatomía, Histología y Neurociencia. Fecha de lectura: 8-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 08-03-2019Las células del tejido nervioso modifican su organización estructural y funcional gracias a una propiedad que se denomina plasticidad neuronal. Datos previos indican que el Sistema Endocrino (SE) ejerce una importante influencia sobre la plasticidad del Sistema Nervioso y, en particular, el éxito de la supervivencia de los mamíferos depende de las adaptaciones que ocurren en el cerebro de la madre a lo largo de la gestación, parto, lactancia y cuidados postnatales. Si bien la Prolactina (PRL) desempeña un importante papel en estas etapas, su capacidad para inducir cambios plásticos en el SN son prácticamente desconocidos. Por lo tanto, el objetivo del presente trabajo de tesis consiste en estudiar los mecanismos celulares, circuitales y los posibles receptores sinápticos involucrados en los cambios plásticos sinápticos inducidos por la PRL en el hipocampo. Empleando técnicas electrofisiológicas extracelulares y de patch-clamp en rodajas de cerebro de ratones así como estudios extracelulares de campo en animales anestesiados, pudimos establecer que la PRL es capaz de modificar la plasticidad sináptica a corto y largo plazo en el hipocampo. Estos cambios se llevan a cabo a través de mecanimos que incluyen la particpación de receptores GABAérgicos, dopaminérgicos, cambios en la probabilidad de liberación de neurotransmisor y la vía de señalización mediada por JAK2. Por otra parte, existe una acción sinérgica entre la PRL y el β-estradiol y la interacción entre estas hormonas es capaz de modular la plasticidad sináptica de la región CA1 en el hipocampo en situaciones en las que la función ovárica está anulada. El presente trabajo constituye a la primera evidencia experimental que se tiene sobre la acción de esta hormona sobre la plasticidad sináptica y a una mejor comprensión de los mecanismos a través de los cuales el SN procesa, almacena yrecupera la información.cells of nervous tissue can modify their structural and functional organization through a property called neuronal plasticity. This enables the nervous system (NS) to perform continuous morphological and synaptic adjustments to create new connections and generate new circuits. Moreover, the endocrine system (ES) and NS are both essential to the communication throughout the body and the maintenance of homeostasis. In most cases, they work in different ways and have different means of transmitting their signals from one place to another but the two systems also overlap and work together in important respects. It is well stablished that ES modulates brain plasticity but it is not clear yet whether hormones, such as prolactin, may regulate functional synaptic plasticity. Therefore, the main aim of the present work was to determine the cellular and molecular mechanisms mediated by prolactin which regulate different forms of synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. Using extracellular and patch-clamp electrophysiological techniques in brain slices of mice as well as extracellular in vivo recordings of urethane anesthetized mice, we have determined that PRL can modify the short and long term synaptic plasticity in hippocampus. These changes are carried out through mechanisms that include GABAergic and dopaminergic receptors regulation, changes in the probability of neurotransmitter release and activation the JAK2-mediated signalling pathway. In addition, we demonstrate that a synergistic action between PRL and β-estradiol can improve the synaptic strength of the CA1 region in the hippocampus under suppression of ovarian function. These findings will enhance our understanding of the mechanisms by which the NS processes, stores and recalls information, thereby facilitating complex processes such as learning in general and particular physiological situation. Furthermore, this knowledge will provide new insight into NS pathologies that involve a deficit in the different forms of learning and memory as well as synaptic and circuital changes that occur in different diseases of NS.Regulación de la plasticidad sináptica en el hipocampo por el sistema endocrino. Papel de la prolactina. Ref: BFU2014-57929-P. Secretaría de Estado de Investigación, Desarrollo e Innovación, Ministerio de Economía y Competitividad, España. IP: Eduardo Daniel Martín Montiel Plasticidad sináptica independiente de receptores NMDA en el hipocampo. Ref: BFU2011-26339. Secretaría de Estado de Investigación, Desarrollo e Innovación, Ministerio de Economía y Competitividad, España. IP: Eduardo Daniel Martín Montie

Neurodevelopmental disorders: 2021 update

One of the current challenges in the field of neurodevelopmental disorders (NDDs) is still to determine their underlying aetiology and risk factors. NDDs comprise a diverse group of disorders primarily related to neuro-developmental dysfunction including autism spectrum disorder (ASD), developmental delay, intellectual dis-ability (ID), and attention-deficit/hyperactivity disorder (ADHD) that may present with a certain degree of cognitive dysfunction and high prevalence of neuropsychiatric outcomes. Last year, advances in human ge-nomics have begun to shed light on the genetic architecture of these disorders and large-scale sequencing studies are starting to reveal mechanisms that range from unique genomic DNA methylation patterns (i.e. “episignatures”) to highly polygenic conditions. In addition, the contribution of de novo somatic mutations to neurodevelopmental diseases is being recognized. However, progressing from genetic findings to underlying neuropathological mechanisms has proved challenging, due to the increased resolution of the molecular and genetic assays. Advancement in modelling tools is likely to improve our understanding of the origin of neuro-developmental disorders and provide insight into their developmental mechanisms. Also, combined in vivo editing of multiple genes and single-cell RNA-sequencing (scRNA-seq) are bringing us into a new era of un-derstanding the molecular neuropathology of NDDs

Neurotrophin receptor p75NTR mediates Huntington's disease-associated synaptic and memory dysfunction

Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype

Análisis de la actividad sináptica en un modelo experimental de actividad epileptiforme

En el trabajo se ha realizado el procesado y análisis de registros de actividad epileptiforme en ratas con el fin de obtener parámetros que aporten información y nos permitan relacionar el comportamiento de la célula en situaciones previas a episodios epilépticos.Zamora Moratalla, A. (2011). Análisis de la actividad sináptica en un modelo experimental de actividad epileptiforme. http://hdl.handle.net/10251/15480Archivo delegad

Neurotrophin receptor p75NTR mediates Huntington's disease-associated synaptic and memory dysfunction

Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD