DCC null mice die within a few hours following birth, making it impossible to study DCC loss-of-function in adults using conventional knockouts. The canonical netrin-1 receptor, deleted in colorectal cancer (DCC), is essential for neural development and widely expressed in the mature nervous system. Further, hippocampal-dependent spatial memory is impaired in mice that conditionally lack netrin-1 expression by principal excitatory forebrain neurons, suggesting that netrin-1 signaling has a critical role in synaptic plasticity underlying hippocampal-dependent spatial memory. In the mature nervous system, conditional deletion of netrin-1 from principal excitatory forebrain neurons impairs activity-dependent plasticity, and bath application of exogenous netrin-1 results in rapid synaptic recruitment of Ca 2+-permeable AMPARs. Accordingly, alteration of dendritic spine structure and synaptic composition can impact neuronal transmission and activity-dependent plasticity.įirst described in the embryonic central nervous system, the secreted chemotropic guidance cue, netrin-1, regulates cytoskeletal reorganization, mediates cell adhesion, and directs cell and axon migration. Brief high-frequency stimulation (HFS) of Schaffer collateral synapses, the primary excitatory efferent connection between CA3 and CA1 pyramidal neurons in the hippocampus, results in a long-lasting change in the strength of synaptic transmission that is mediated primarily through the modification and membrane recruitment of excitatory postsynaptic receptors on dendritic spines. Long-term potentiation (LTP) is an extensively studied form of activity-dependent synaptic plasticity. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in the intrinsic electrophysiological properties of CA1 pyramidal neurons, but impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and LTP at Schaffer collateral synapses. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons resulted in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, weaker spontaneous excitatory postsynaptic activity, and reduced levels of postsynaptic adaptor and signaling proteins however, the capacity to induce LTP remained intact. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. DCC co-fractionates with the detergent-resistant component of postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development.
![hippocampus anatomy mouse hippocampus anatomy mouse](https://i.ytimg.com/vi/wY0XWBFcxQA/maxresdefault.jpg)
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.
![hippocampus anatomy mouse hippocampus anatomy mouse](https://onlinelibrary.wiley.com/cms/asset/4c64fe15-f156-4e8c-ac86-531eb866a26f/jon12809-fig-0001-m.jpg)
![hippocampus anatomy mouse hippocampus anatomy mouse](https://d3i71xaburhd42.cloudfront.net/7279ced1c40b569f8d7eb7e53a7da04b9471f652/13-Figure1.1-1.png)
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.