Synaptic-Driven Changes in Intrinsic Excitability of Layer V Pyramidal Neurons

突触驱动的第五层锥体神经元内在兴奋性的变化

• 批准号: 8127208
• 负责人: Brian E. Kalmbach
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127208
• 关键词: Action Potentials; Affect; Alzheimer' s Disease; Attention; Attention deficit hyperactivity disorder; Autistic Disorder; Bathing; Cells; Cognitive; Data; Dendrites; Dependence; Disease; Epilepsy; Frequencies; Functional disorder; Gated Ion Channel; Goals; Grant; Hippocampus (Brain); Learning; Maintenance; Measures; Medial; Mediating; Membrane; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neuromodulator; Neurons; Neurotransmitter Receptor; Neurotransmitters; Output; Prefrontal Cortex; Process; Property; Receptor Activation; Research; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Site; Somatic Cell; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Work; base; cyclic-nucleotide gated ion channels; hippocampal pyramidal neuron; insight; nervous system disorder; neuronal cell body; patch clamp; relating to nervous system; research study; response; treatment strategy; voltage

DESCRIPTION (provided by applicant): The input/output properties of a neuron are modifiable. Characterizing changes in input/output properties is imperative to understanding how neural activity changes in response to ongoing changes in network activity. While there are several examples of input-driven changes in neural excitability, it is not known how ongoing synaptic activity modulates the input/output properties of a neuron. The long-term goal of the proposed research is characterize how ongoing synaptic input affects the integrative properties of layer V pyramidal neurons in prefrontal cortex (PFC). The first specific aim of this proposal will further test the initial observation that low rates of synaptic stimulation produce changes in the excitability of pyramidal neurons in layer V of PFC. These experiments will identify the conductances and neurotransmitter receptors involved in the observed changes. These experiments involve whole-cell patch clamp recordings from the soma of layer V PFC neurons. The second specific aim will test the hypothesis that the changes occur in the dendrites in a manner that depends on the frequency and site of stimulation. Completion of this aim will provide insight into whether the plasticity is short-term or long-term and whether it is homeostatic or putatively involved in learning. These experiments will involve both whole-cell somatic and dendritic recordings. The third specific aim will test for differences in changes in the properties of two classes of neurons with different repertoires of membrane conductances: those that project within the cortex and those that project subcortically. The overriding hypothesis of this specific aim is that changes in input/output properties depend on the specific membrane conductances available to be modified. PUBLIC HEALTH RELEVANCE: Understanding how ongoing synaptic input affects the input/output properties of a neuron could have implications for treatment strategies for a variety of disorders associated with changes in neural excitability including epilepsy. In addition, the prefrontal cortex is involved in several cognitive processes such as action planning and working memory. Thus, characterizing changes in prefrontal neurons is vital for developing treatment strategies for a host of neurological disorders associated with deficits in these cognitive processes, including: Alzheimer's disease, attention disorders such as ADHD, autism, and schizophrenia.

描述（由申请人提供）：神经元的输入/输出属性是可修改的。表征输入/输出属性的变化对于理解神经活动如何响应网络活动的持续变化至关重要。虽然有几个输入驱动的神经兴奋性变化的例子，但尚不清楚持续的突触活动如何调节神经元的输入/输出特性。拟议研究的长期目标是表征持续突触输入如何影响前额皮质 (PFC) 中第五层锥体神经元的整合特性。该提案的第一个具体目标将进一步测试最初的观察结果，即低速率的突触刺激会导致 PFC 第五层锥体神经元的兴奋性变化。这些实验将确定所观察到的变化所涉及的电导和神经递质受体。这些实验涉及来自第五层 PFC 神经元体的全细胞膜片钳记录。第二个具体目标将检验以下假设：树突中发生的变化取决于刺激的频率和部位。完成这一目标将有助于深入了解可塑性是短期的还是长期的，以及它是稳态的还是假定与学习有关。这些实验将涉及全细胞体细胞和树突记录。第三个具体目标将测试具有不同膜电导库的两类神经元的特性变化的差异：在皮层内投射的神经元和在皮层下投射的神经元。这一特定目标的首要假设是输入/输出特性的变化取决于可修改的特定膜电导。 公共健康相关性：了解持续的突触输入如何影响神经元的输入/输出特性可能会对与神经兴奋性变化（包括癫痫）相关的各种疾病的治疗策略产生影响。此外，前额叶皮层还参与多种认知过程，例如行动计划和工作记忆。因此，表征前额叶神经元的变化对于制定针对与这些认知过程缺陷相关的一系列神经系统疾病的治疗策略至关重要，这些疾病包括：阿尔茨海默氏病、注意力缺陷多动障碍、自闭症和精神分裂症。