Impact of human disease-causing mutation on striatal synaptic and behavioral plasticity

人类致病突变对纹状体突触和行为可塑性的影响

基本信息

批准号：
10037918
负责人：
Deanna L Benson
金额：
$ 2.93万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10037918
关键词：
Adult Affect Attention Attentional deficit Axon Behavior Behavioral Biological Assay Biology Brain Cell physiology Cerebral cortex Cognitive Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Data Dendritic Spines Development Diagnostic Disease Progression Dorsal Equilibrium Exhibits Genes Genetic Glutamates Goals Head Heritability Human Impaired cognition Impairment Impulsivity Knock-in Knock-in Mouse Knowledge LRRK2 gene Learning Life Link Location Molecular Motor Mus Mutation Neurobiology Neurons Neurophysiology - biologic function Operant Conditioning Parkinson Disease Pathogenicity Pathway interactions Pharmacology Phosphotransferases Point Mutation Population Signal Pathway Signal Transduction Stimulus Structure Substantia nigra structure Symptoms Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Time Ventral Striatum base behavioral outcome behavioral plasticity classical conditioning clinical Diagnosis cognitive function cognitive task disease-causing mutation dopaminergic neuron experimental study flexibility human disease in vivo insight kinase inhibitor motor symptom mutant neural circuit non-motor symptom novel postnatal progressive neurodegeneration psychiatric symptom small molecule synaptic function synaptogenesis therapy development tool young adult

项目摘要

PROJECT SUMMARY The G2019S mutation is the most common of several mutations in leucine-rich repeat kinase 2 (LRRK2) causing up to 40% of familial Parkinson's disease in certain populations. This pathogenic point mutation is autosomal dominant and increases kinase activity 2-3 fold. Disease progression in both motor and non-motor symptoms of mutant LRRK2 carriers is similar to idiopathic cases suggesting common mechanisms, but progress has been limited because LRRK2 biology is poorly understood and little is known of pathogenic cellular or synaptic actions of G2019S-LRRK2. LRRK2 expression is high in spiny projection neurons (SPNs) of dorsal and ventral striatum, and rises rapidly during axon ingrowth and excitatory synaptogenesis. The timing and location of expression suggests that mutant LRRK2 may be maladaptively influencing development of excitatory circuits that impact striatal function. To begin to test this idea, we probed glutamatergic synaptic function in SPNs in G2019S-LRRK2 knockin mice. We showed that early in postnatal life, G2019S-SPNs in dorsal striatum exhibit a significantly abnormal increase in spontaneous excitatory synaptic currents (sEPSCs) compared to WT mice or mice expressing a LRRK2 kinase-dead knockin mutation (D2017A). Such abnormal excitatory activity was observed in both direct- and indirect-pathway SPNs, was normalized by LRRK2 kinase inhibitors, and was associated with larger SPN dendritic spine-heads and sEPSC amplitudes. Dorsal striatal SPNs receive convergent input from cerebral cortex and control many types of goal- directed behaviors, and the latter are thought to reflect balanced control of bidirectional changes in corticostriatal synaptic strength. The early abnormalities in SPN synaptic function and structure suggest that synaptic plasticity will be altered by G2019S-LRRK2 with consequences for striatally-based behaviors. Preliminary data support both of these ideas. Together, we hypothesize that the normal balance between mechanisms that strengthen or weaken synaptic transmission is altered in SPNs expressing G2019S-LRRK2 in a way that both reveals molecular signaling pathways targeted by mutant LRRK2 and that has predictable consequences for behaviors. The proposed experiments will assess the impact of mutant LRRK2 on synapse strengthening and weakening in subtype-identified SPNs; they will identify the molecular pathways and mechanisms involved; they will determine if mutant LRRK2 alters behaviors associated with SPN synapse plasticity; and they will test whether in vivo LRRK2 inhibition early in life ameliorates maladaptive effects on synaptic and behavioral plasticity documented later in life.

项目概要 G2019S 突变是富含亮氨酸重复激酶 2 的几种突变中最常见的一种 (LRRK2) 在某些人群中导致高达 40% 的家族性帕金森病。这个致病点突变为常染色体显性突变，激酶活性增加 2-3 倍。运动和疾病进展突变型 LRRK2 携带者的非运动症状与特发性病例相似，表明存在共同机制，但由于人们对 LRRK2 的生物学知之甚少，而且对其致病性知之甚少，因此进展有限。 G2019S-LRRK2 的细胞或突触作用。 LRRK2 在背侧和腹侧纹状体的棘投射神经元 (SPN) 中表达较高，并且升高在轴突向内生长和兴奋性突触发生过程中迅速发生。表达的时间和地点表明突变体 LRRK2 可能会不适应地影响影响纹状体的兴奋性回路的发育功能。为了开始测试这个想法，我们探测了 G2019S-LRRK2 中 SPN 的谷氨酸突触功能敲入小鼠。我们发现，在出生后早期，背侧纹状体中的 G2019S-SPN 表现出显着的与 WT 小鼠或小鼠相比，自发兴奋性突触电流 (sEPSC) 异常增加表达 LRRK2 激酶死亡敲入突变 (D2017A)。观察到这种异常兴奋活动在直接和间接途径 SPN 中，通过 LRRK2 激酶抑制剂使其正常化，并且与具有较大的 SPN 树突棘头和 sEPSC 振幅。背侧纹状体 SPN 接收来自大脑皮层的汇聚输入并控制多种类型的目标定向行为，后者被认为反映了对双向变化的平衡控制皮质纹状体突触强度。 SPN 突触功能和结构的早期异常表明 G2019S-LRRK2 将改变突触可塑性，并对基于纹状体的行为产生影响。初步数据支持这两个想法。我们共同假设，之间的正常平衡表达 G2019S-LRRK2 的 SPN 中增强或减弱突触传递的机制发生了改变以一种既揭示了突变体 LRRK2 靶向的分子信号传导途径又具有可预测性的方式行为的后果。拟议的实验将评估突变体 LRRK2 对突触的影响亚型识别的 SPN 的增强和减弱；他们将识别分子途径并涉及的机制；他们将确定突变的 LRRK2 是否会改变与 SPN 突触相关的行为可塑性;他们将测试生命早期的体内 LRRK2 抑制是否会改善对突触和行为可塑性在以后的生活中被记录下来。