The neocortex consists of billions of neurons with trillions of connections, and is responsible for cognitive tasks such as perception and abstract reasoning. Cortical abnormalities are associated with devastating neuropsychiatric illnesses including autism spectrum disorders and schizophrenia, further underscoring the importance of understanding how the cortex functions. Despite major advances in understanding the properties of individual neurons, we are just beginning to understand the rules that govern the assembly of neocortical circuits. One major unanswered question in the field is whether molecular mechanisms direct the wiring diagram of neural circuits at the level of individual cells. In other words, is there a genetic blue print that governs the local wiring of cortical circuits? Tis question is technically challenging to address because it will require simultaneous analysis of both neuronal connectivity and the gene expression profile at the level of single cortical neurons. Moreover, it will require massive amounts of data to be collected as well as advanced analysis techniques to crack the molecular code of connectivity. We propose to use multi-whole-cell patch clamp recording combined with single-cell reverse transcription (RT)-PCR to investigate whether the clustered protocadherin gene family provides a molecular code for neural circuit assembly. The clustered protocadherins have been shown to be expressed in a combinatorial code in individual neurons, are highly expressed during synaptogenesis, and localize to synapses. Thus, clustered protocadherins are the leading candidate molecules for shaping neocortical circuits. However, their role in instructing specific synapse formation has not been directly tested due to the difficulty of these types of experiments. Furthermore, the challenging aspects of this project make it unlikely to be funded by more traditional mechanisms. The results of these experiments could revolutionize our understanding of neural circuit assembly and lead to a more principled approach to studying neuropsychiatric disorders at the circuit level.

Public Health Relevance

This study aims to test the hypothesis that there is a molecular code that governs the connectivity of cortical circuits. Abnormal connectivity in neocortical networks is thought to underlie many neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism spectrum disorder. Discovering the molecular code of connectivity in the cortex will provide us with the genetic blue print to study how cortical circuits are assembled and promises to also provide a paradigm shift for studying neuropsychiatric disorders at the circuit level.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-M (07))
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Beckel-Mitchener, Andrea C
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Baylor College of Medicine
Schools of Medicine
United States
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Cadwell, Cathryn R; Sandberg, Rickard; Jiang, Xiaolong et al. (2017) Q&A: using Patch-seq to profile single cells. BMC Biol 15:58
Duman, Joseph G; Tu, Yen-Kuei; Tolias, Kimberley F (2016) Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity. Neural Plast 2016:8301737
Cadwell, Cathryn R; Palasantza, Athanasia; Jiang, Xiaolong et al. (2016) Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol 34:199-203