Autism spectrum disorder (ASD) is a pervasive but poorly understood neurological disorder. Timothy Syndrome, a disorder with a highly significant link to ASD, has recently been shown to have a monogenetic origin in a single nucleotide substitution within the L-type Ca2+ channel. This mutation prolongs channel opening, an effect that can be mimicked pharmacologically by the L-type Ca2+ channel agonist BayK 8644. In this way we can recapitulate TS in an animal model to generate findings that can potentially generalize to other ASDs. This animal model allows for a detailed investigation of TS from molecular mechanisms to hippocampal circuitry. The goal of this proposal is to characterize the effects of BayK 8644 on physiological processes in the hippocampus at multiple levels from synapses to circuits and to provide a roadmap for how a single molecular malfunction can affect the functioning of a neural circuit leading to a disease phenotype.l.
Specific Aim 1 - To test the hypothesis that BayK 8644 leads to enhanced activation of a postsynaptic Ca2+-activated K+ conductances during excitatory synaptic transmission. We have demonstrated that BayK 8644 has a dampening effect on excitatory synaptic transmission in acute slices of rat hippocampus. We propose a series of experiments to characterize the cellular physiology underlying this surprising effect. II.
Specific Aim 2 - To develop a system for studying behaviorally relevant network dynamics in a hippocampal slice preparation. We have developed a novel system using multi-unit tetrode recordings to study pattern separation in an acute hippocampal slice. Using this well-controlled slice preparation, we propose to probe the network transition point between pattern completion and pattern separation. III.
Specific Aim 3 - To test the hypothesis that BayK 8644 interferes with hippocampal circuit dynamics by upsetting the balance of excitatory and inhibitory influences in the circuit. By applying BayK 8644 during a series of experiments similar to those described in Aim 2, we propose to test how the behaviorally relevant circuit dynamics are affected in an acute model of autism spectrum disorder. We will combine intracellular and tetrode recordings in order to connect the subcellular to the macroscopic effects of this disease model.

Public Health Relevance

Autism spectrum disorder is a common and profoundly debilitating psychological disorder. While recent evidence has implied a genetic basis for this disease, we know very little about how to connect genes to function to [eventually] treatment. We propose here a series of experiments to develop a deeper understanding of how one model of autism spectrum disorder might function at multiple levels from genes to molecules to neural circuits as they function in the brain.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03B-L (20))
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Vogel, Michael W
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Stanford University
Schools of Medicine
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Owen, Scott F; Tuncdemir, Sebnem N; Bader, Patrick L et al. (2013) Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500:458-62
Wheeler, Damian G; Groth, Rachel D; Ma, Huan et al. (2012) Ca(V)1 and Ca(V)2 channels engage distinct modes of Ca(2+) signaling to control CREB-dependent gene expression. Cell 149:1112-24
Bader, Patrick L; Faizi, Mehrdad; Kim, Leo H et al. (2011) Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A 108:15432-7