Neurodevelopmental disorders with Prof. Michele Jacob

December 3, 2024·36 min·2 clips

APC knockout mice keep burying marbles, circling, and failing to habituate.

1. NeuroPodCases' episode "Neurodevelopmental disorders with Prof. Michele Jacob" centers on APC, beta-catenin, and Wnt signaling in brain development. 2. Dr. Michael Cairns and Filippo Dallarmellina host Prof. Michelle Jacob, a Tufts University neuroscientist whose lab studies developmental brain disorders. 3. The episode asks how a synaptic protein study turned into a translational program for autism spectrum disorder, intellectual disability, and CTNNB1 syndrome. 4. Jacob says her lab began with nicotinic cholinergic synapses and an unbiased screen that pulled in APC. 5. APC mutations in the literature brought seizures and cognitive issues into view, which pushed the lab into conditional knockout mice. 6. Those APC mice showed learning disabilities, autism-like behaviors, reduced hearing, severe epilepsy, and infantile spasms. 7. Jacob then built gain-of-function and loss-of-function beta-catenin models to separate APC loss from increased beta-catenin. 8. She explains that global beta-catenin knockout is embryonic lethal, so the lab used CAMK2-Cre in excitatory neurons during the late embryonic and first three postnatal weeks. 9. That timing maps onto the human third trimester, when glutamatergic neurons are differentiating and autism-linked genes are turning on. 10. A March 2020 Frontiers in Synaptic Neuroscience paper reported that excessive beta-catenin in excitatory neurons reduced social behavior and increased repetitive behavior. 11. Jacob describes the three-chamber assay, social-memory testing, and odor habituation as ways to measure mouse social interest. 12. She also describes marble burying, circling, nest building, and pup care as readouts that separated the APC and beta-catenin models from wild-type mice. 13. The Barnes maze section shows how the mice learned spatial cues around a 40-hole table and how the mutants wandered more chaotically. 14. Jacob says elevated beta-catenin changed genes tied to axon guidance, learning and memory, and Parvalbumin neuron levels. 15. She notes that manipulating beta-catenin in excitatory neurons also altered inhibitory neurons through soluble signaling, shifting excitatory-inhibitory balance. 16. The CTNNB1 syndrome work moved the lab toward a full-body heterozygous mouse, patient-derived cells, and high-specificity GSK3 inhibitors. 17. Jacob and the hosts keep the conversation technical but practical, moving from molecular pathways to behavioral assays, mouse genetics, and patient cells. 18. The interview format is measured and collaborative, with Cairns and Dallarmellina repeatedly asking for experimental detail and translational implications. 19. Listeners interested in autism genetics, synaptic biology, and mouse-model methods will get the most from this episode. 20. Listeners wanting a light, nontechnical chat or a spoiler-free biology primer may skip it.

As heard by us

A grounded look at how Wnt signaling and mouse behavior inform developmental brain disorder research.

NeuroPodCases brings developmental brain disorders into a focused molecular frame, using Professor Michelle Jacob's work on autism spectrum disorders and intellectual disability to trace the canonical Wnt signaling pathway.

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You can hear autism-relevant mouse behaviors turn into data, then follow canonical Wnt signaling toward therapeutic possibility.

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