Identification of GPR55 cellular expression within hippocampal cells and its phys

海马细胞内 GPR55 细胞表达及其生理结构的鉴定

• 批准号: 8289139
• 负责人: JEFFREY G EDWARDS
• 金额: $ 36.25万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289139
• 关键词: Accounting; Agonist; Alzheimer' s Disease; Attenuated; Binding; Biological; Brain; Brain region; Calcium; Cell physiology; Cells; Data; Disease; Electrophysiology (science); Endocannabinoids; Environment; Epilepsy; Evolution; Functional disorder; GTP-Binding Proteins; Glutamates; Goals; Health; Hippocampus (Brain); Immunohistochemistry; Interneurons; Knockout Mice; Learning; Living Costs; Long-Term Potentiation; Marijuana; Mediating; Memory; Messenger RNA; Molecular; N-Methyl-D-Aspartate Receptors; Neurons; Orphan; Pathologic; Pathway interactions; Pattern; Phenotype; Physiological; Physiology; Play; Proteins; Pyramidal Cells; Rattus; Reporting; Research Proposals; Role; Seizures; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Time; anandamide; attenuation; cannabinoid receptor; experience; immunocytochemistry; lysophosphatidylinositol; mRNA Expression; neurotransmission; novel; presynaptic; protein expression; receptor; research study; response

DESCRIPTION (provided by applicant): The hippocampus is the brain region mediating learning and memory. Hippocampal dysfunction disorders, which include Alzheimer's disease and epilepsy, are a significant health problem disrupting life and costing millions of dollars. Recently, endocannabinoids (eCBs) were suggested as candidates to treat Alzheimer's disease for beneficial effects on the evolution of the disease and alleviating symptoms. In addition, eCBs are an excellent target for antiepileptogenesis because eCB receptors are often presynaptic and decrease excitatory transmitter release thus mitigating excitatory seizure activity. The cellular process of hippocampal learning and memory is synaptic plasticity. Synaptic plasticity or changes in synaptic activity occur in response to afferent input from our senses, allowing for us to respond and adapt to changes and experiences in our environment. Currently, several important pathways were demonstrated to play a role in modulating plasticity, including eCBs and eCB receptors. The primary eCB receptor in the brain is cannabinoid receptor 1 (CB1). This receptor for example impairs memory by decreasing plasticity when activated by THC, the active component in marijuana. While many have studied the effect of CB1 on synaptic plasticity, there are other eCB pathways/receptors involved in plasticity not accounted for by CB1. These accounts were described as being from a 'non-CB1' or unidentified CB3 receptor because CB1 (nor CB2) was involved. However, this 'non-CB1' receptor (possibly one or more receptors) has not been correlated to a particular receptor type. In order to fully understand how a 'non-CB1' receptor is influencing hippocampal plasticity and thus learning and memory, we must first identify what this receptor is. One excellent candidate for this receptor is the yet to e classified orphan G protein receptor, GPR55, because it is expressed in the brain and is functionally active. Importantly, GPR55 binds eCBs such as anandamide. The main goal of this research proposal is to investigate GPR55 and related receptors as putative hippocampal eCB receptors that modulate hippocampal plasticity, and thus memory formation. We will first use quantitative real-time PCR and immunocytochemistry to examine cellular expression of hippocampal GPR55 mRNA and protein. Then using whole cell and field electrophysiology we will examine the involvement of GPR55 in modulation of excitatory synaptic transmission and altering hippocampal synaptic plasticity, namely long-term potentiation. The broad long-term goals of this project are to better understand the role eCBs, especially novel eCB receptors, play in modulating hippocampal function and plasticity with a view towards alleviating some of the complications associated with pathologic states in the hippocampus including Alzheimer's disease and epilepsy. PUBLIC HEALTH RELEVANCE: Alzheimer's and epilepsy are disease states that occur in the hippocampus, the brain region involved in learning and memory, which is mediated by synaptic plasticity, critical for memory. Endocannabinoids modulate hippocampal synaptic plasticity and therefore memory as well as epilepsy, however, many endocannabinoid pathways exist in the hippocampus have not been identified. Our goal is to investigate a novel receptor we believe to be involved in endocannabinoid- mediated modulation of synaptic plasticity with a view towards applying what we learn towards alleviating deficits in disease states such as Alzheimer's and epilepsy.

描述（由申请人提供）：海马是介导学习和记忆的大脑区域。包括阿尔茨海默病和癫痫在内的海马神经功能障碍是一个严重的健康问题，扰乱了人们的生活，造成数百万美元的损失。最近，内源性大麻素（eCB）被建议作为治疗阿尔茨海默病的候选药物，对疾病的发展和缓解症状具有有益的影响。此外，eCB是抗癫痫发生的极好靶点，因为eCB受体通常是突触前的，并减少兴奋性递质释放，从而减轻兴奋性癫痫发作活动。海马学习记忆的细胞过程是突触可塑性。突触可塑性或突触活动的变化发生在对我们感官的传入输入的反应中，允许我们对环境中的变化和体验做出反应和适应。目前，几个重要的途径被证明在调节可塑性中发挥作用，包括eCB和eCB受体。大脑中的主要eCB受体是大麻素受体1（CB 1）。例如，当被大麻中的活性成分THC激活时，这种受体通过降低可塑性来损害记忆。虽然许多人已经研究了CB 1对突触可塑性的影响，但还有其他参与可塑性的eCB通路/受体未被CB 1解释。这些账户被描述为来自“非CB 1”或未识别的CB 3受体，因为涉及CB 1（或CB 2）。然而，这种“非CB 1”受体（可能是一种或多种受体）与特定的受体类型无关。为了充分了解“非CB 1”受体如何影响海马可塑性，从而影响学习和记忆，我们必须首先确定这种受体是什么。这种受体的一个很好的候选者是尚未分类的孤儿G蛋白受体GPR 55，因为它在大脑中表达并且具有功能活性。重要的是，GPR 55结合eCB，例如大麻素。本研究的主要目标是研究GPR 55和相关受体作为假定的海马eCB受体，调节海马可塑性，从而记忆形成。我们将首先使用定量实时PCR和免疫细胞化学来检测海马GPR 55 mRNA和蛋白的细胞表达。然后，使用全细胞和场电生理学，我们将检查GPR 55参与兴奋性突触传递的调制和改变海马突触可塑性，即长时程增强。该项目的广泛长期目标是更好地了解eCB，特别是新型eCB受体在调节海马功能和可塑性方面的作用，以期减轻与海马病理状态相关的一些并发症，包括阿尔茨海默病和癫痫。 公共卫生关系：阿尔茨海默氏症和癫痫是发生在海马体中的疾病状态，海马体是参与学习和记忆的大脑区域，其由突触可塑性介导，对记忆至关重要。内源性大麻素调节海马突触可塑性，因此记忆和癫痫，然而，许多内源性大麻素途径存在于海马尚未确定。我们的目标是研究一种我们认为参与内源性大麻素介导的突触可塑性调节的新型受体，以期将我们所了解的应用于减轻阿尔茨海默病和癫痫等疾病状态的缺陷。

项目成果

Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat.

• DOI: 10.3390/ijms241311193
• 发表时间: 2023-07-07
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Winzenried, Eric T.;Everett, Anna C.;Saito, Erin R.;Miller, Roxanne M.;Johnson, Taylor;Neal, Eliza;Boyce, Zachary;Smith, Calvin;Jensen, Chloe;Kimball, Spencer;Brantley, Adam;Melendez, Gabriel;Moffat, Devin;Davis, Erin;Aponik, Lyndsey;Crofts, Tyler;Dabney, Bryson;Edwards, Jeffrey G.
• 通讯作者: Edwards, Jeffrey G.

Running exercise mitigates the negative consequences of chronic stress on dorsal hippocampal long-term potentiation in male mice.

• DOI: 10.1016/j.nlm.2018.01.008
• 发表时间: 2018-03
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Miller RM;Marriott D;Trotter J;Hammond T;Lyman D;Call T;Walker B;Christensen N;Haynie D;Badura Z;Homan M;Edwards JG
• 通讯作者: Edwards JG

Expression of type I mGluRs predicts plasticity in the hippocampal stratum radiatum interneurons.

I 型 mGluR 的表达预测海马放射层中间神经元的可塑性。

• DOI: 10.1016/j.neulet.2019.134472
• 发表时间: 2019
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Nufer,TeresaM;Merrill,Collin;Friend,Lindsey;Hopkins,Zach;Boyce,Zach;Edwards,JeffreyG
• 通讯作者: Edwards,JeffreyG

Identification of mRNA for endocannabinoid biosynthetic enzymes within hippocampal pyramidal cells and CA1 stratum radiatum interneuron subtypes using quantitative real-time polymerase chain reaction.

• DOI: 10.1016/j.neuroscience.2012.05.012
• 发表时间: 2012-08-30
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Merrill, C. B.;McNeil, M.;Williamson, R. C.;Poole, B. R.;Nelson, B.;Sudweeks, S.;Edwards, J. G.
• 通讯作者: Edwards, J. G.

Acute cocaine exposure occludes long-term depression in ventral tegmental area GABA neurons.

• DOI: 10.1016/j.neuint.2021.105002
• 发表时间: 2021-05
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Friend LN;Wu B;Edwards JG
• 通讯作者: Edwards JG