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

• 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
• 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

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.

项目总结 G2019S突变是富含亮氨酸的重复蛋白激酶2的几个突变中最常见的 (LRRK2)在某些人群中导致高达40%的家族性帕金森病。本病穴 突变是常染色体显性的，使激酶活性增加2-3倍。运动和运动的疾病进展 突变LRRK2携带者的非运动症状类似于特发性病例，提示共同的机制， 但进展有限，因为人们对LRRK2生物学知之甚少，致病机制也知之甚少。 G2019S-LRRK2的细胞或突触作用。 LRRK2在背侧和腹侧纹状体的棘突投射神经元(SPN)中高表达，并呈上升趋势 在轴突生长和兴奋性突触形成过程中迅速生长。表达的时间和地点表明 该突变体LRRK2可能不适应地影响影响纹状体的兴奋回路的发育 功能。为了开始验证这一观点，我们探索了G2019S-LRRK2中SPN中的谷氨酸能突触功能 诺克金老鼠。我们发现，在出生后早期，背侧纹状体中的G2019S-SPN表现出显著的 WT小鼠和WT小鼠自发兴奋性突触电流(SEPSCs)的异常增加 表达LRRK2激酶-死亡敲击突变(D2017A)。观察到了这种异常的兴奋活动 在直接和间接途径的SPN中，LRRK2激酶抑制剂使其正常化，并与 具有较大的SPN树突棘头部和sEPSC波幅。 背侧纹状体SPN接受大脑皮层的汇聚性输入，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提示 突触可塑性将被G2019S-LRRK2改变，从而导致基于纹状体的行为。 初步数据支持这两种观点。我们共同假设，正常的平衡在 表达G2019S-LRRK2的SPN中加强或减弱突触传递的机制发生改变 这两种方式都揭示了突变体LRRK2靶向的分子信号通路，并具有可预测性 行为的后果。拟议的实验将评估突变的LRRK2对突触的影响 亚型识别的SPN的增强和减弱；它们将识别分子途径和 涉及的机制；他们将确定突变的LRRK2是否改变与SPN突触相关的行为 他们将在体内测试在生命早期抑制LRRK2是否可以改善对 突触和行为可塑性在后来的生活中被记录下来。