Teneurin-3 and Latrophilin-2 in circuit-wide topographic target selection of the extended hippocampal network

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PROJECT SUMMARY The central nervous system is made up a vast number of neurons connected into the circuits that underlie all brain function. Precise circuit assembly is accomplished, in part, through axonal target selection, mediated by cell surface molecules (CSMs) that serve as recognition tags to identify appropriate synaptic partners. However, the sheer volume of synapses that must be constructed for a healthy brain outstrips the number of available coding genes by orders of magnitude. One way to mitigate this challenge is through molecular gradients such that connections are specified by a relative amount of one molecule instead of by individual molecules. Another is to reuse the same CSMs in different anatomical regions. The goal of this proposal is to leverage the stereotyped, topographical connections of the extended hippocampal network to examine if one receptor-ligand CSM pair can mediate precise assembly of all nodes of a functional circuit. The extended hippocampal network consists of connections between CA1, subiculum (Sub), entorhinal cortex (EC), mammillary nucleus (mMN), and the anteroventral thalamus (AVT). Each node is further subdivided into parallel medial and lateral hippocampal networks (MHN and LHN, respectively). By postnatal day 8 (P8), all five of these regions have inverse gradients of the CSMs, Teneurin-3 (Ten-3) and Latrophilin-2 (Lphn-2), restricted to MHN and LHN, respectively. This complementary expression suggests a ‘Ten3→Ten3, Lphn2→Lphn2’ connectivity rule. In fact, for the CA1→Sub projection, Ten3-expressing CA1 axons appear to be attracted to Sub-derived Ten3 and repelled by Sub-derived Lphn2 to precisely target the MHN subdivision of CA1. Conversely, Lphn2-expressing CA1 axons are repelled by Sub-derived Ten3 to target the LHN. Circuit-wide inverse Ten3 and Lphn2 expression suggests these mechanisms could be reused broadly. This proposal will assess if the mechanisms of Ten3 homophilic attraction and Ten3-Lphn2 heterophilic repulsion are recapitulated at each anatomical node within the extended hippocampal network to mediate precise topographical circuit assembly. Using a combination of genetic and viral techniques, Ten3 or Lphn2 will be conditionally deleted from each origin and target region in a series of loss of function manipulations followed by viral circuit-tracing to assess mistargeting. This study represents the first test of a single receptor-ligand pair mediating the circuit assembly of an entire functional network. Disruption in wiring is a hallmark of many neurodevelopment and psychiatric disorders, so elucidating the molecular mechanisms of circuit assembly may lead to therapeutic strategies pertinent to the NIMH mission. Along with the research aims in this proposal, this fellowship will support additional training technical expertise, scientific writing, mentorship, and career development. Stanford University will provide the ideal well-equipped, intellectually diverse, and collaborative environment to complete the proposed study.