Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex

The ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that conditional genetic deletion of netrin-1 or the netrin receptor deleted-in-colorectal cancer (DCC) from forebrain excitatory neurons leads to deficits in short-term spatial memory. We then demonstrate that conditional deletion of either netrin-1 or DCC inhibits cholinergic persistent firing and show that cholinergic activation of muscarinic receptors expressed by entorhinal cortical neurons promotes persistent firing by recruiting DCC to the plasma membrane. Together, these findings indicate that normal short-term spatial memory function requires the synergistic actions of acetylcholine and netrin-1. [Display omitted] •Deletion of netrin-1 or its receptor DCC perturbs spatial working memory•Netrin-1 loss impairs cholinergic persistent firing in layer V entorhinal cortex•Cholinergic activation increases surface DCC to generate plateau potentials•Netrin-1 and cholinergic activation synergize to generate persistent firing Glasgow et al. show that loss of netrin-1 or DCC disrupts short-term spatial memory and is required for cholinergic persistent firing, a cellular substrate for working memory. Cholinergic receptor activation recruits plasma membrane DCC, which works synergistically with netrin-1 to promote cationic-channel-mediated plateau potentials in layer V entorhinal neurons.