Aim 1: Investigate the ASD related symptoms caused by CTNNB1 deletion from PV neurons
Our preliminary data demonstrated that Ctnnb1 KO in PV neurons may cause deficits mimicking some core symptoms in ASD patients. Since repetitive behavior is another core symptom in ASD patients, we will further test the repetitive behaviors using grooming test, marble bury, and nesting building. Moreover, many autism patients show learning disabilities. To measure learning and memory in our mouse model, we will examine short-/ long-term memory, working memory, recognition memory and spatial memory using contextual fear conditioning, T-maze, novelty recognition test and Morris-Water Maze.
Aim 2: Determine the underlying mechanisms caused by PV neuron specific …show more content…
This leads to the imbalance between excitatory and inhibitory circuitry in the brain. To determine how Ctnnb1 KO caused the abnormal inhibitory circuitry, we will exam the number, and localization of PV neurons and other interneurons, such as calbindin, somatostatin interneurons, in our mouse model. Ctnnb1 plays a critical role in synaptogenesis(9). Yet, how it regulates formation of inhibitory synapses is not clear. We will monitor the effect of Ctnnb1 KO on the number and shape of inhibitory spine in PV neurons. Moreover, by collaborating with Dr. Gong, whose lab has extensive experience in electrophysiology, we will measure the spontaneous postsynaptic current, miniature excitatory postsynaptic current (mEPSC), inhibitory PSC, induction of long-term potentiation (LTP) and long-term depression (LTD). To monitor whether Ctnnb1 KO in PV neurons affects the overall neuronal activities, we will cross GCaMP reporter mice with our KO model and use calcium imaging to quantitatively measure neuronal …show more content…
We have developed a mouse model with Ctnnb1 KO in PV interneurons to better understand the underlying mechanism of Ctnnb1 in pathophysiology of ASD. The major gap in current knowledge that we will address in this proposal is to determine how PV neuron- specific Ctnnb1 KO affects animal behaviors and to what extent Wnt agonist can reverse the behavioral deficits. Lack of such knowledge makes it difficult to design a strategy for ASD risk genes involved in the Wnt pathway. We expect to identify the circuitry defect that is involved in PV neurons specific Ctnnb1 knockout mice and examine the extent to which targeting Wnt pathway would be able to ameliorate the behavioral deficits. This contribution will be significant because it is the critical step to allow control the Wnt signaling pathway in the interneurons and may lead to the development of a pharmacologic approach to correct ASD-related behavioral defects, thereby improving the life for ASD patients. What is learned in this proposal will be applicable to other ASDs caused by mutations associated with the Wnt pathway, such as CHD8. Thus, our research will make a significant step towards the development of therapies for ASD carrying Ctnnb1 deficiency or other ASDs that are associated with mutations in the Wnt pathway. In addition, our proposal will contribute to a broader understanding of the regulation of inhibitory
Our preliminary data demonstrated that Ctnnb1 KO in PV neurons may cause deficits mimicking some core symptoms in ASD patients. Since repetitive behavior is another core symptom in ASD patients, we will further test the repetitive behaviors using grooming test, marble bury, and nesting building. Moreover, many autism patients show learning disabilities. To measure learning and memory in our mouse model, we will examine short-/ long-term memory, working memory, recognition memory and spatial memory using contextual fear conditioning, T-maze, novelty recognition test and Morris-Water Maze.
Aim 2: Determine the underlying mechanisms caused by PV neuron specific …show more content…
This leads to the imbalance between excitatory and inhibitory circuitry in the brain. To determine how Ctnnb1 KO caused the abnormal inhibitory circuitry, we will exam the number, and localization of PV neurons and other interneurons, such as calbindin, somatostatin interneurons, in our mouse model. Ctnnb1 plays a critical role in synaptogenesis(9). Yet, how it regulates formation of inhibitory synapses is not clear. We will monitor the effect of Ctnnb1 KO on the number and shape of inhibitory spine in PV neurons. Moreover, by collaborating with Dr. Gong, whose lab has extensive experience in electrophysiology, we will measure the spontaneous postsynaptic current, miniature excitatory postsynaptic current (mEPSC), inhibitory PSC, induction of long-term potentiation (LTP) and long-term depression (LTD). To monitor whether Ctnnb1 KO in PV neurons affects the overall neuronal activities, we will cross GCaMP reporter mice with our KO model and use calcium imaging to quantitatively measure neuronal …show more content…
We have developed a mouse model with Ctnnb1 KO in PV interneurons to better understand the underlying mechanism of Ctnnb1 in pathophysiology of ASD. The major gap in current knowledge that we will address in this proposal is to determine how PV neuron- specific Ctnnb1 KO affects animal behaviors and to what extent Wnt agonist can reverse the behavioral deficits. Lack of such knowledge makes it difficult to design a strategy for ASD risk genes involved in the Wnt pathway. We expect to identify the circuitry defect that is involved in PV neurons specific Ctnnb1 knockout mice and examine the extent to which targeting Wnt pathway would be able to ameliorate the behavioral deficits. This contribution will be significant because it is the critical step to allow control the Wnt signaling pathway in the interneurons and may lead to the development of a pharmacologic approach to correct ASD-related behavioral defects, thereby improving the life for ASD patients. What is learned in this proposal will be applicable to other ASDs caused by mutations associated with the Wnt pathway, such as CHD8. Thus, our research will make a significant step towards the development of therapies for ASD carrying Ctnnb1 deficiency or other ASDs that are associated with mutations in the Wnt pathway. In addition, our proposal will contribute to a broader understanding of the regulation of inhibitory