Kroc Lecture - Carla Shatz

During brain development, circuits form sequentially, initially by creating a basic scaffold of connectivity according to strict molecular guidance cues. Subsequently the final details of each circuit emerge by pruning and sculpting synapses. This synapse selection process is also genetically specified but in this case the program requires neural activity. Prenatally, the brain generates its own internal neural activity patterns to jump-start the sculpting process. Postnatally, experience of the world takes over to sharpen brain wiring during critical periods. Neural activity and sensory experience regulate expression of sets of genes including several previously thought to act only in the immune system. These genes, including Major Histocompatibility Class I family members and a cognate receptor Paired immunoglobulin-like receptor B (PirB), are expressed in cortical and hippocampal neurons and are required for activity-dependent synapse pruning and plasticity. Memories are stored at synapses and circuits, which are lost and destroyed in Alzheimer's disease (AD). Unexpectedly, PirB and its human homolog LilrB2 are also high affinity receptors for soluble oligomers of beta amyloid. In human cerebral cortex, LilrB2 is expressed in neurons and at excitatory synapses, and is also present in neurons in human cortical organoids. It could be that well before amyloid plaque formation, excessive levels of soluble beta amyloid put normal synapse pruning mediated by PirB/LilrB2 into overdrive. PirB KO knockout protects AD model mice from cognitive loss and alterations in Hebbian synaptic plasticity. Thus, changes in expression and/or function of these molecules may contribute to synapse pruning disorders in neurodegenerative disease, as well as in development. Supported by NIH EY02858, NIA AG065206, Mathers Charitable Foundation, Sapp Family Foundation, Phil and Penny Knight Stanford Initiative for Brain Resilience.

,