Autism spectrum disorders (ASDs) have risen to approximately 1 in 88 in the Unites States over the past years, affecting an entire generation of children, families and communities. Currently, the diagnosis for most forms of ASD is based on a triad of behavioral symptoms, including social impairments, communication difficulties, and repetitive or stereotyped behaviors, with no quantitative measures for screening or assessment of potential drug therapies. Electrophysiological measurements of synapses and neuronal networks from these patients may hold the potential for diagnosing, characterizing and analyzing the effectiveness of potential treatment strategies. Here, we propose to apply a transformative technology for the long-term intracellular recording networks of neurons differentiated from patient-derived iPSC. To accomplish this goal, we have created a solid-state device comprised of 2D arrays of Stealth electrodes that sit passively within the membrane of neuronal cells and have the capacity to record synaptic, neuronal and network properties of multiple interconnected neurons simultaneously for days to weeks. Through the optimization of the fabrication of these Stealth probes and the transformation into a turn-key device, we will evaluate the feasibility of this platform as a diagnostic and research tool for ASD. We then propose to use this innovative scalable analytical platform to characterize the neuronal, synaptic and network signatures of neurons differentiated from iPS cells derived from patients with Phelan-McDermid Syndrome and then assess the effectiveness of emerging drug therapies to normalize aberrant signatures. If successful, our solid-state platform can be transformed into a high-throughput screening device that will allow investigators to recapitulate early developmental stages of ASD and evaluate the effects of ASD mutations and environmental insults on neuronal network and synaptic function and utilize this as a tool for drug screening, diagnosis and personalized treatment.
Psychiatric and neurodevelopmental disorders with complex, multigenic causes, such as autism spectrum disorders (ASDs) and schizophrenia, have long frustrated scientists and clinicians seeking quantitative measures for diagnosis and effective pharmacotherapies. Electrophysiological measurements of neurons from induced pluripotent stem cells (iPSCs) derived from ASD patients hold the potential of diagnosing, characterizing, and assessing the effectiveness of emerging treatment strategies based on electrophysiological signatures of synapses and neuronal networks. Here we have designed a new solid-state electrophysiology recording architecture based on Stealth electrodes that permit stable recordings of synaptic and network properties of many neurons simultaneously and allow for the characterization of neurons derived from patients with Phelan-McDermid Syndrome and assessment of emerging drug therapies to normalize aberrant properties.
|Ha, Huong; Huguenard, John (2016) Criminal Minds: Cav3.2 Channels Are the Culprits, but NMDAR Are the Co-Conspirators. Epilepsy Curr 16:36-8|
|Deleuze, Charlotte; Huguenard, John R (2016) Two classes of excitatory synaptic responses in rat thalamic reticular neurons. J Neurophysiol 116:995-1011|
|Arons, Magali H; Lee, Kevin; Thynne, Charlotte J et al. (2016) Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength. J Neurosci 36:9124-34|