Maladaptive compensatory plasticity in developing cortical circuits

皮质回路发育中的适应不良代偿可塑性

• 批准号: 10163974
• 负责人: Sacha B Nelson
• 金额: $ 3.61万
• 依托单位: BRANDEIS UNIVERSITY
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163974
• 关键词: Address; Affect; Angelman Syndrome; Animals; Array tomography; Biological Assay; Brain; Brain Diseases; Cells; Chromatin; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Epilepsy; Equilibrium; Excitatory Synapse; Exhibits; Family member; Financial compensation; Fragile X Syndrome; Functional Imaging; Gene Expression; Gene Expression Profiling; Genetic Transcription; Global Change; Image; Imaging Techniques; Individual; Inhibitory Synapse; Intellectual functioning disability; Interneurons; Knock-out; Knockout Mice; Lead; Methods; Monitor; Mus; Neocortex; Neurons; Pathway interactions; Pattern; Physiological; Proteins; Rattus; Recovery; Regulation; Resolution; Risk; Role; Seizures; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Testing; Transcriptional Regulation; Up-Regulation; audiogenic seizure; autism spectrum disorder; base; cell type; critical period; deprivation; design; developmental disease; experimental study; hippocampal pyramidal neuron; imaging study; improved; in vivo; in vivo monitoring; loss of function; mouse model; neocortical; novel; prevent; response; selective expression; single-cell RNA sequencing; transcription factor; transcriptome sequencing

Project Summary Abstract Developmental disorders including Autism Spectrum Disorders and Intellectual Disability can lead to reduced cortical activity. Paradoxically, these same disorders also greatly increase the risk for developing seizures. Multiple homeostatic plasticity mechanisms can compensate for reduced activity by increasing excitatory synaptic transmission and cellular excitability, and/or by decreasing inhibitory synaptic transmission. But these normally beneficial mechanisms can have maladaptive effects, especially when reduced activity is prolonged and occurs early, during a critical period of circuit formation. For example, activity blockade in vivo in rat or mouse neocortex, induces seizures, but only if it occurs early and for a prolonged period. Here we explore the mechanisms underlying this Maladaptive Compensatory Plasticity (MCP) in cultured neocortical slices. Activity blockade produces a qualitative change in subsequent synchronized activity that persists following prolonged deprivation when activity is restored. This is accompanied by a dramatic shift in the balance between excitation and inhibition. Physiological and imaging studies are consistent with a dramatic change in synaptic connectivity. Aim 1 will identify the critical physiological features of MCP, that separate it from normal homeostatic plasticity. By blocking activity in single neurons, and by varying the timing and duration of activity blockade, we will distinguish cell autonomous from network effects, and determine which are critical for persistent effects of MCP. Using synapse imaging techniques and paired recording, we ask whether induction of MCP alters the number of functional excitatory and inhibitory synapses. Aims 2 develops the novel idea of push/pull transcriptional regulation of homeostatic plasticity. We identify a pair of closely related transcription factors (TFs) that are potently and progressively upregulated during blockade of activity. Intriguingly, these TFs are part of a pathway that opposes compensatory plasticity, since compensatory responses are exaggerated when they are knocked out. CRISPR-based manipulations will be used to alter TF expression selectively in specific cell types. RNAseq will be used to identify candidate targets, and chromatin assays will distinguish direct and indirect targets. Finally, we will initiate in vivo studies to more directly test the role of homeostatic plasticity and its transcriptional regulation in audiogenic seizures. Together these studies may identify new strategies for mitigating maladaptive consequences of normally beneficial plasticity mechanisms.

项目摘要