Memory modulation by SK channels

通过 SK 通道进行内存调制

• 批准号: 7902027
• 负责人: ROBERT WILLIAM STACKMAN
• 金额: $ 35.53万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902027
• 关键词: Affect; Aging; Amygdaloid structure; Anxiety Disorders; Apamin; Biology; Brain; Brain region; Calcium; Calcium-Activated Potassium Channel; Coupled; Cues; Data; Dendritic Spines; Development; Dorsal; Excision; Excitatory Postsynaptic Potentials; Extinction (Psychology); Fright; Glutamate Receptor; Goals; Hippocampus (Brain); Infusion procedures; Injection of therapeutic agent; Intervention; Knowledge; Lateral; Learning; Long-Term Potentiation; Mediating; Memory; Memory Loss; Memory impairment; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Receptor Activation; Research Personnel; Retrieval; Rodent; Role; SK potassium channel; Shapes; Shunt Device; Staging; Surface; Synapses; Synaptic plasticity; Testing; Training; Work; channel blockers; cohort; combat; conditioned fear; density; improved; insight; interdisciplinary approach; memory acquisition; memory encoding; memory process; morris water maze; nervous system disorder; neuronal excitability; novel; overexpression; postsynaptic; public health relevance; research study; response

DESCRIPTION (provided by applicant): Treating the devastating loss of memory associated with aging or neurodegenerative disease requires that we first understand the basic cellular mechanisms of memory. Small conductance calcium-activated potassium (SK) channels play a fundamental role in shaping the responses of neurons in brain regions known to be critical for memory. SK channels are also functionally coupled to a well recognized cellular mechanism of memory, the NMDA-type glutamate receptor. NMDA receptor activity is considered by many to be essential for synaptic changes that underlie memory formation. Activation of SK channels reduces excitatory NMDA receptor responses and shunts NMDA receptor-dependent synaptic plasticity. Therefore, SK channels are in a unique position to influence memory processes. The goals of this application are to understand: A) the distinct influence of SK channels in the hippocampus and in the lateral amygdala on the processes of memory encoding, retention, retrieval and extinction; B) the consequence of specific blockade of SK2 channels, or the specific activation of SK3 and SK2 channels on hippocampal and amygdala memory processes; C) the efficacy of SK channel blockers to rescue the memory deficits found in mice that overexpress SK2 channels; and D) the potential for dendritic SK2 channels in the lateral amygdala to be internalized after the encoding of new fear memories. These experiments combine Pavlovian fear conditioning paradigms with region-specific intracranial microinfusions to define the influence of brain SK channels on memory processes. The final aim involves a collaborative effort with Dr. John Adelman (Co- Investigator) to conduct ultrastructural analyses of synapses of lateral amygdala neurons after fear conditioning. Our preliminary findings indicate that the SK channel blocker, apamin enhances memory, while the SK channel activator, 1-EBIO impairs memory. Evidence also suggests that memory encoding or the formation of new memory is uniquely sensitive to SK channel blockers and activators. The lack of effect of SK channel drugs on later stages of memory suggests that SK channels may undergo a form of plasticity during learning - perhaps removal from the dendritic spine surface. Together, the proposed studies will provide insights into the relatively underdeveloped field of memory modulation. The studies will improve knowledge of the mechanisms involved in distinct memory processes, including extinction of memory. These studies will also contribute to defining targets for novel therapies to combat impairments of memory that result from aging and neurological disorders, a well as treatments for fear and anxiety disorders. PUBLIC HEALTH RELEVANCE: The proposed studies will provide insights into the fundamental basic biology of memory. The project will highlight mechanisms of several memory processes and aid the development of novel therapies to combat impairments of memory that result from aging, neurodegenerative disorders, and fear or anxiety disorders.

描述（由申请人提供）：治疗与衰老或神经退行性疾病相关的毁灭性记忆丧失，要求我们首先了解记忆的基本细胞机制。小电导钙激活的钾（SK）通道在塑造已知对记忆至关重要的大脑区域的神经元反应方面起着基本作用。 SK通道在功能上也与良好的记忆的细胞机制，NMDA型谷氨酸受体耦合。许多人认为NMDA受体活性对于基于记忆形成的突触变化至关重要。 SK通道的激活减少了兴奋性NMDA受体反应，并分流NMDA受体依赖性突触可塑性。因此，SK通道处于影响记忆过程的独特位置。该应用的目标是理解：a）海马中SK通道和侧杏仁核在记忆编码，保留，检索和灭绝过程中的明显影响； b）SK2通道的特定阻滞的结果，或海马和杏仁核记忆过程上SK3和SK2通道的特定激活； c）SK通道阻滞剂挽救过表达SK2通道的记忆缺陷的功效； d）在编码新的恐惧记忆后，侧杏仁核中树突状SK2通道的潜力被内化。这些实验结合了Pavlovian恐惧调节范式与区域特异性颅内微觉得，以定义脑SK通道对记忆过程的影响。最终目的涉及与约翰·阿德曼（John Adelman）博士（合伙人）的合作努力，以在恐惧调节后进行侧向杏仁核神经元突触的超微结构分析。我们的初步发现表明，SK通道阻滞剂Apamin增强了内存，而SK通道激活器1-EBIO会损害内存。证据还表明，记忆编码或新内存的形成对SK通道阻滞剂和激活器非常敏感。 SK通道药物在记忆后期的缺乏的影响表明，SK通道可能会在学习过程中经历一种形式的可塑性 - 也许可以从树突状脊柱表面去除。拟议的研究将共同​​提供对相对欠发达的内存调制领域的见解。研究将提高对不同记忆过程中涉及的机制的了解，包括记忆的灭绝。这些研究还将有助于定义新型疗法，以打击衰老和神经系统疾病所致的记忆障碍，这是恐惧和焦虑症的治疗方法。公共卫生相关性：拟议的研究将为记忆的基本生物学提供见解。该项目将重点介绍几种记忆过程的机制，并有助于开发新型疗法，以打击衰老，神经退行性疾病以及恐惧或焦虑症导致的记忆障碍。