Abstract
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 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 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. 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. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory.
Highlights
Long-term potentiation (LTP) is an extensively studied form of activity-dependent synaptic plasticity [1]
To investigate whether deleted in colorectal cancer (DCC) contributes to synaptic transmission in the adult brain through distinct pre- and post-synaptic mechanisms, we selectively deleted a floxed dcc allele from either CA3 or CA1 excitatory pyramidal neurons by Cre expression regulated by Grik4 (Grik4-Cre/DCCfl/fl) or R4ag11 (R4ag11-Cre/DCCfl/fl) promoters, respectively
We demonstrate that conditional deletion of DCC from CA1 pyramidal neurons significantly impaired spatial memory tasks, reduced spontaneous EPSCs (sEPSCs) amplitude, altered dendritic spine morphology, and reduced levels of SHANK2, SHANK3, postsynaptic density 95 (PSD-95), p34-Arc, and phosphorylated S6 ribosomal proteins compared to control wild-type littermates, but did not block high-frequency stimulation (HFS)-induced LTP at Schaffer collateral synapses
Summary
Long-term potentiation (LTP) is an extensively studied form of activity-dependent synaptic plasticity [1]. 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 Ca2+-permeable AMPARs [7]. Hippocampal-dependent spatial memory is impaired in mice that conditionally lack netrin-1 expression by principal excitatory forebrain neurons [8], suggesting that netrin-1 signaling has a critical role in synaptic plasticity underlying hippocampal-dependent spatial memory. Mice selectively lacking DCC expression by CA3 glutamatergic neurons showed impaired spatial memory accompanied by reduced basal excitatory synaptic transmission and attenuated HFS-induced LTP. Our findings suggest that these deficits may be due to reduced DCC-mediated presynaptic vesicular mobilization in CA3 neurons, and reveal distinct pre- and postsynaptic functions for DCC at Schaffer collateral synapses contributing to synaptic plasticity underlying memory consolidation in the adult brain
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