Autism Spectrum Disorder (ASD) is a neuropsychiatric disorder that affects millions of individuals in the United States. Individuals with ASD have perseverative and restrictive behaviors, with social and language deficits. While there has been significant progress in understanding the genetics of ASD, the underlying cause of autism remains unknown. Recent work has suggested that a form of plasticity - homeostatic plasticity - is altered in ASD. Homeostatic plasticity is a way for the brain to change itself with the goal of keeping it stable. My research attempts to dissect how ASD-associated mutations affect a neuron’s ability to use homeostatic plasticity, with the hopes that it will help us understand the pathophysiological underpinnings of autism. This project is currently funded by the National Institutes of Health, NIMH: 1F31MH115611-01 Characterizing maladaptive homeostasis in an animal model of ASD.
the timing of homeostatic plasticity
The brain cannot function properly if it isn’t stable.
Your brain is always changing. Whenever you learn something new or remember something old, the neurons in your brain modify their connections - synapses. But with each changing synapse, a neuron becomes less and less stable. With homeostatic plasticity, your neurons rebalance themselves so that new incoming information can be integrated. In fact, neuroscientists think that homeostasis is crucial for basic brain functioning (some think it’s why we need to sleep!). Improper homeostatic plasticity has been linked with many neuropsychiatric diseases: autism, schizophrenia, and epilepsy. Many things are still unknown about homeostatic plasticity, one of which is how it changes over time. My research is attempting to dissect which neuronal properties are regulated by homeostasis and how this changes over long periods of time. This image is showing electrical current entering neurons, giving us an idea of how strong its synapses are.
planar cell polarity signaling in axon pathfinding
Sun SD, Purdy AM, Walsh GS. Planar cell polarity genes Frizzled3a, Vangl2, and Scribble are required for spinal commissural axon guidance. BMC Neurosci. 2016 Dec 12;17(1):83. PubMed PMID: 27955617
The development of the nervous system is an incredibly complex, yet beautiful process. Neurons are born and immediately begin to form the circuits and structures necessary for proper brain formation. Neurons send chemical and electrical signals to other neurons through their axon, but before they can, they must find their target neurons. This process is achieved through Axon Pathfinding. Axon pathfinding during development is crucial for proper brain formation. Because the human and mammalian brains are so complex and take a very long time to form, I used zebrafish, a transparent animal that develops quickly to understand how axon pathfinding is controlled. I discovered that neurons in the spinal cord need a certain kind of molecular signaling in order to pathfind properly. This type of signaling is know as Planar Cell Polarity (PCP). PCP is a way a developing organism sets up it's internal compass. It tells other cells which way is up, down, left, or right. Without PCP, neurons do not know where to go or where to send their axons. My research determined that specific members of the PCP signaling pathway are important for axon pathfinding. These are various images I took of spinal cord neurons in developing fishes.
scribble localization through development
Sun, SD. Planar Cell Polarity in Neurodevelopment [Master's Thesis]. [Richmond (VA)]: Virginia Commonwealth University; 2014. 81p. Available from: VCU Library ETDs, Richmond, VA.
Planar Cell Polarity (PCP) is a form of cellular and molecular signaling that provides a directional "compass" for cells. Without proper PCP signaling, cells in the body don't know where they are in the body, or which direction they're facing (toward the head or toward the tail, left or right, up or down). PCP signaling utilizes many different genes and proteins that all play a specific role in making the body's compass. Scribble is one such PCP protein. It was first discovered in fruit flies. When scribble is mutated, the body of developing fruit flies become all scribbled up! Hence the name! My studies focused on identifying where scribble is located inside cells through various stages of development. I discovered that scribble primarily localizes as small punctate structures on many cell membranes and is important for the formation of specific neuronal structures. This image marks Scribble in red, contrasted by a neuron marked in teal. I discovered that scribble is found in small sub cellular structures in the extensions of neurons.