Synaptic Plasticity in Neural Development and Neurodevelopmental Disorders
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Our memories are formed through experiences that leave an indelible trace in the brain. Scientists have appreciated that sensory experience is not only necessary for the formation of memories, but sensory experience is also required for the proper development of the brain. During a critical period of development, experience-evoked neural activity refines synaptic connections so that appropriate connections are strengthened and maintained while inappropriate connections are weakened and eventually eliminated. In this manner, sensory experience helps transform an immature neural network into one that extracts meaningful information from the environment. We aim to characterize both how experience shapes synaptic plasticity during development such that stable and appropriate synaptic connections are formed, and how this process can go awry in neurodevelopmental disorders such as Angelman syndrome and autism spectrum disorders.
We take advantage of the visual cortex and the hippocampus to examine properties of experience- and activity-dependent synaptic plasticity. The strengthening and weakening of synapses have been termed long-term potentiation (LTP) and long-term depression (LTD), respectively, and are thought to be a natural consequence of patterned neural activity.
Our laboratory is currently working on two main projects: (1) the synaptic basis for Angelman syndrome and autism spectrum disorders, and (2) the role of NMDA receptors in neural development.
1. The synaptic basis for Angelman syndrome and autism spectrum disorders
We have been studying the synaptic basis for autism-related disorders, with our main focus on Angelman syndrome, which is considered by many to be an autism spectrum disorder. Angelman syndrome is a severe mental retardation caused by the maternal deletion of the UBE3A gene, which encodes an E3 ubiquitin ligase that targets specific proteins for proteosomal degradation. Angelman syndrome is characterized by a lack of speech and a high incidence of seizures. The apparent lack of neurodegeneration and the sharp postnatal onset of symptoms in Angelman syndrome has suggested a developmental defect in synaptic circuits, whose origin is unknown. Our laboratory has recently demonstrated that Ube3a is required for experience-dependent maturation of neocortical circuits. We are now working to define the synaptic basis for this dysfunction, with the expectation that this will help us design rational therapies for the treatment of Angelman syndrome. We are also working on a small molecule screen to activate the epigentically-silenced UBE3A allele, with the hope that this will reveal drug treatments for Angelman syndrome.
2. Role of NMDA receptors in neural development
Another focus of our laboratory is to examine how NMDA receptor localization and composition affects the properties of synaptic plasticity (LTP and LTD) so that the visual world can be properly analyzed. To address this question, we employ techniques such as electrophysiology to examine how visual experience shapes synaptic function. We also take advantage of genetically engineered mice to test specific hypotheses of synaptic plasticity. We aim to fully characterize experience-dependent modifications in excitatory synaptic transmission in cortical layers 2/3, the initial site for receptive field plasticity. Because activation of the NMDA-type glutamate receptor (NMDAR) is required for receptive field plasticity and the induction of LTP/LTD, we hypothesize that changes in NMDAR function might regulate the properties of synaptic plasticity. Included among the questions our lab is addressing are: (1) How does experience modify the molecular composition and localization of neocortical NMDA receptors? (2) What is the role of presynaptic NMDA receptors in synaptic transmission and plasticity? (3) What is the role of the novel NMDA receptor subunit, NR3A, in regulating synapse maturation, function, and plasticity? (4) By what mechanism does visual experience regulate the properties of synaptic plasticity?
These studies will characterize how experience regulates the elementary properties of plasticity and excitatory synaptic transmission. We hope to unlock mechanisms for restoring synaptic plasticity in visual cortex that had been rendered dysfunctional due to amblyopia. Moreover, it is our hope that heuristics learned in the visual cortex might be generally applicable to synaptic plasticity associated with development, drug addiction, and/or learning and memory. Accordingly, we also study some aspects of synaptic function and plasticity in the hippocampus and prefrontal cortex.
Techniques employed in the laboratory
The lab has grown tremendously in the last several years, and through collaborations at Duke and UNC we have incorporated a number of new techniques into our laboratory. Currently our lab is performing the following techniques:
• Whole-cell electrophysiology under IR-DIC visual guidance
• Field potential recordings
• Construction and characterization of knock-in and transgenic mice (with Mark Zylka’s lab @ UNC)
• Molecular biology and cell culture
• Pharmacology of synaptic responses
• Immunofluorescence-based laser capture microdissection
• Biochemistry of subcellular fractionation (including PSD purification)
• Immunofluorescence staining
• Small molecule screens (in collaboration with Bryan Roth’s lab @ UNC)
• Behavioral phenotyping (with the core facility run by Sheryl Moy @ UNC)
• Lentiviral knockdown and overexpression of constructs (with Mike Ehler’s lab @ Duke University)
Send inquiry and CV to Dr. Philpot by email.