Pre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus

The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of the postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons results in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, and weaker spontaneous excitatory postsynaptic activity. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in spine morphology or intrinsic electrophysiological properties of CA1 pyramidal neurons, but resulted in impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral synapse. Together, these findings reveal that DCC makes specific pre- and post-synaptic contributions to hippocampal synaptic plasticity underlying spatial memory.