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Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the postnatal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory. Here, we assessed the impact of neuronal expression of netrin-1 in the adult brain on behavior using tests of learning and memory. We show that adult mice exhibit impaired spatial memory following conditional deletion of netrin-1 from glutamatergic neurons in the hippocampus and neocortex. Further, we provide evidence that mice with conditional deletion of netrin-1 do not display aberrant anxiety-like phenotypes and show a reduction in self-grooming behavior. These findings reveal a critical role for netrin-1 expressed by neurons in the regulation of spatial memory formation.

Adult neural plasticity engages mechanisms that change synapse structure and function, yet many of the underlying events bear a striking similarity to processes that occur during the initial establishment of neural circuits during development. It is a long‐standing hypothesis that the molecular mechanisms critical for neural development may also regulate synaptic plasticity related to learning and memory in adults. Netrins were initially described as chemoattractant guidance cues that direct cell and axon migration during embryonic development, yet they continue to be expressed by neurons in the adult brain. Recent findings have identified roles for netrin‐1 in synaptogenesis during postnatal maturation, and in synaptic plasticity in the adult mammalian brain, regulating AMPA glutamate receptor trafficking at excitatory synapses. These findings provide an example of a conserved developmental guidance cue that is expressed by neurons in the adult brain and functions as a key regulator of activity‐dependent synaptic plasticity. Notably, in humans, genetic polymorphisms in netrin‐1 and its receptors have been linked to neurodevelopmental and neurodegenerative disorders. The molecular mechanisms associated with the synaptic function of netrin‐1 therefore present new therapeutic targets for neuropathologies associated with memory dysfunction. Here, we summarize recent findings that link netrin‐1 signalling to synaptic plasticity, and discuss the implications of these discoveries for the neurobiological basis of memory consolidation. [ABSTRACT FROM AUTHOR]