HCN1 channels in hippocampal function and spatial memory

描述（由申请人提供）：海马体（一个对陈述性学习和记忆很重要的脑区）功能障碍与多种精神和神经障碍有关，包括阿尔茨海默病、精神分裂症、抑郁症和癫痫。海马回路中的长时程突触可塑性与学习和记忆都有广泛的联系，并且是疾病的潜在原因。然而，相对知之甚少的是如何整合的海马神经元的膜特性有助于空间信息处理或疾病的过程。该提议关注HCN 1超极化激活通道对空间学习和记忆的贡献，HCN 1超极化激活通道在海马CA 1锥体神经元的树突中高度表达，在那里它调节突触整合。HCN 1是进一步的兴趣，因为它的表达水平是动态调节神经活动。事实上，已经提出在癫痫发作期间HCN 1的下调有助于癫痫的发展。HCN 1在脑功能中的作用先前在一系列小鼠中进行了研究，其中HCN 1在前脑中被选择性地删除。令人惊讶的是，这些小鼠在空间学习和记忆方面表现出增强。这种行为效应与突触传递和长时程增强（LTP）在直接皮质，temperoammonic（TA）输入到CA 1神经元，其终止于远端CA 1树突，HCN 1的表达通常是最大的增强。这些结果表明，HCN 1提供了一个抑制性限制在TA突触的突触可塑性和空间学习和记忆。然而，HCN 1约束这些过程的机制尚不清楚。此外，相对较少的是已知的突触可塑性或其行为意义的TA突触，在主要谢弗侧支输入CA 1神经元的突触可塑性的信息相比，财富。这个建议代表了一个多学科的研究，结合在体内记录的CA 1神经元活动与海马切片记录TA突触可塑性和双光子成像的钙在远端CA 1树突，以解决以下问题：如何HCN 1删除增强LTP在TA突触？它是否改变了远端树突钙峰的放电--这与LTP有关？TA LTP是否与远端树突中HCN 1表达的动态变化相关，这是否改变了突触传递？HCN 1是否通过影响CA 1神经元中空间信息的体内编码来限制空间学习和记忆？通过关注在CA 1神经元树突的特定区域中富集的特定离子通道的作用，本研究将有助于阐明HCN 1及其在空间记忆编码中调节的定义的突触元件的作用。这些研究可能会验证HCN 1通道作为癫痫，年龄相关性记忆丧失，重度抑郁症，精神分裂症和海马功能相关疾病的新疗法的潜在目标。

DESCRIPTION (provided by applicant): Disorders in the function of the hippocampus, a brain region important for declarative learning and memory, have been implicated in a variety of psychiatric and neurological disorders, including Alzheimer's disease, schizophrenia, depression and epilepsy. Long-term synaptic plasticity in hippocampal circuits has been widely implicated in both learning and memory and as an underlying cause of disease. However, comparatively little is known about how the integrative membrane properties of hippocampal neurons contribute to spatial information processing or disease processes. This proposal focuses on the contribution to spatial learning and memory of the HCN1 hyperpolarization-activated channel, which is highly expressed in the dendrites of hippocampal CA1 pyramidal neurons where it regulates synaptic integration. HCN1 is of further interest as its level of expression is dynamically regulated by neural activity. Indeed, downregulation of HCN1 during seizures has been proposed to contribute to development of epilepsy. The role of HCN1 in brain function was previously studied in a line of mice in which HCN1 was deleted selectively in the forebrain. Surprisingly, these mice showed an enhancement in spatial learning and memory. This behavioral effect was associated with an enhancement in synaptic transmission and long-term potentiation (LTP) at the direct cortical, temperoammonic (TA) inputs to CA1 neurons, which terminate on the distal CA1 dendrites where HCN1 expression is normally greatest. These results indicate that HCN1 provides an inhibitory constraint on both synaptic plasticity at the TA synapses and on spatial learning and memory. However, the mechanism by which HCN1 constrains these processes is not known. Moreover, relatively little is known about synaptic plasticity or its behavioral significance at the TA synapses, compared to the wealth of information on synaptic plasticity at the major Schaffer collateral inputs to CA1 neurons. This proposal represents a multidisciplinary study, combining in vivo recordings of CA1 neuronal activity with hippocampal slice recordings of TA synaptic plasticity and two-photon imaging of calcium in distal CA1 dendrites, to address the following questions: How does HCN1 deletion enhance LTP at TA synapses? Does it alter the firing in the distal dendrites of calcium spikes - events that have been implicated in LTP? Is TA LTP associated with dynamic changes in HCN1 expression in the distal dendrites and does this alter synaptic transmission? Does HCN1 constrain spatial learning and memory by affecting the in vivo encoding of spatial information in CA1 neurons? By focusing on the role of a specific ion channel that is enriched in a specific region of CA1 neuron dendrites, this study will help elucidate the role of HCN1 and the defined synaptic element that it regulates in the encoding of spatial memory. Such studies may validate the HCN1 channel as a potential target for novel therapies for epilepsy, age-related memory loss, major depression, schizophrenia and related diseases of hippocampal function.