The role of semaphorin 3A signaling underlying learning and memory formation in the postnatal mouse brain

Abstract

Memory formation is largely mediated by changes to synapses, which are sites of communication found between neurons. Currently, the dominant experimental model that describes the cellular changes that occur during learning and memory is known as long-term potentiation (LTP). While some of the intracellular signaling cascades underlying learning and memory have been well-described, key molecular pathways remain less well understood. Semaphorins are a family of secreted and membrane-bound guidance cue proteins originally identified in the developing nervous system through their chemorepulsive action at growth cones. Growth cones are actin-rich structures found at the tips of neurites that eventually form synaptic connections, and semaphorins were shown to trigger collapse and retraction of these growth cones, altering the ability to form synaptic connections. Specifically, Semaphorin 3A (Sema3A) is a secreted guidance cue protein implicated both in axonal, through the action at growth cones, and dendritic, through dendritic elongation and spine maturation, refinement. This occurs when Sema3A activates a holoreceptor complex composed of neuropilin-1 (NRP1) / PlexinA4 (PLXNA4), leading to changes in cytoskeletal architecture by way of altering collapsin response mediator protein 2 (CRMP2). Sema3A signaling has been studied extensively in the developing nervous system, though much less is known about its role in the adult brain. Specifically with respect to spatial learning, brain areas including the hippocampus and regions of the cortex have been implicated. Here, NRP1 and CRMP2 signaling are described across postnatal development in the mouse hippocampus and cortex, with protein expression decreasing after birth, increasing at day P28, and persisting into older adulthood. We also show that canonical Sema3A signaling is activated in the mouse hippocampus following spatial learning on a novel object place recognition (NOPR) task, suggesting that Sema3A signaling is critical for the consolidation of spatial information. Together, these findings suggest that Sema3A signaling continues to play a key role in the mature nervous system.