The transmembrane protein deleted in colorectal cancer (DCC) and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP), intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR) function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory.

The ionic conductances underlying membrane potential oscillations of hippocampal CA1 interneurons located near the border between stratum lacunosum-moleculare and stratum radiatum (LM) were investigated using whole cell current-clamp recordings in rat hippocampal slices. At 22 degrees C, when LM cells were depolarized near spike threshold by current injection, 91% of cells displayed 2-5 Hz oscillations in membrane potential, which caused rhythmic firing. At 32 degrees C, mean oscillation frequency increased to 7.1 Hz. Oscillations were voltage dependent and were eliminated by hyperpolarizing cells 6-10 mV below spike threshold. Blockade of ionotropic glutamate and GABA synaptic transmission did not affect oscillations, indicating that they were not synaptically driven. Oscillations were eliminated by tetrodotoxin, suggesting that Na+ currents generate the depolarizing phase of oscillations. Oscillations were not affected by blocking Ca2+ currents with Cd2+ or Ca2+-free ACSF or by blocking the hyperpolarization-activated current (Ih) with Cs+. Both Ba2+ and a low concentration of 4-aminopyridine (4-AP) reduced oscillations but TEA did not. Theta-frequency oscillations were much less common in interneurons located in stratum oriens. Intrinsic membrane potential oscillations in LM cells of the CA1 region thus involve an interplay between inward Na+ currents and outward K+ currents sensitive to Ba2+ and 4-AP. These oscillations may participate in rhythmic inhibition and synchronization of pyramidal neurons during theta activity in vivo.

Cholinergic and GABAergic medial septal afferents contribute to hippocampal theta activity in part by actions on local interneurons. Interneurons near the border between stratum radiatum and stratum lacunosum-moleculare (LM) display intrinsic membrane potential oscillations at theta frequency when depolarized near threshold. First, whole-cell current-clamp recordings in rat hippocampal slices were used to examine effects of the cholinergic agonist carbachol on biocytin-labeled LM interneurons. At resting membrane potential, cells were depolarized by bath application of 25 microM carbachol, and the depolarization was sufficient to induce membrane potential oscillations (2.4 +/- 0.2 mV) that paced cell firing. Carbachol also depolarized LM interneurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione, (+/-)-2-amino-5-phosphonopentanoic acid, and bicuculline, indicating that cholinergic depolarization of LM cells does not depend on ionotropic glutamate or GABA(A) synaptic transmission in local circuits. Atropine blocked the depolarization, indicating that muscarinic receptors were involved. Minimal stimulation applied to visually identified LM interneurons was then used to determine if spontaneous activity in CA1 pyramidal cells can be paced by rhythmic inhibition generated by LM cells at theta frequency. Inhibitory postsynaptic potentials evoked in pyramidal cells by single minimal stimulations were followed by rebound depolarizations and action potentials. When trains of minimal stimulation were delivered, membrane potential oscillations of depolarized pyramidal cells followed the stimulation frequency. Minimal stimulation led pyramidal cell firing with an average phase of 177 degrees. Thus, muscarinic induction of theta-frequency membrane potential oscillations in LM interneurons may contribute to the generation of rhythmic inhibition that paces intrinsically generated theta activity in CA1 pyramidal cells.

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Repeated, daily tetanization of the corpus callosum induces lasting changes in sensorimotor cortex field potential responses, but the synaptic populations that mediate these responses and support long-term potentiation (LTP) have not been characterized. Current source density analyses of field responses were compared between control animals and those in which LTP was induced by 10 daily series of tetanizations. Tetanization and paired-pulse stimulation (100 ms interval) enhanced the duration of initial (∼3 ms onset) deep-negative population spike activity generated by a current sink in layer V that peaked repeatedly at a frequency of ∼400 Hz. The early (∼10 ms to peak) surface-negative component of field responses was generated by a current sink in upper layer V and a source in layer VI. This monosynaptic component followed high stimulation frequencies, recovered quickly from the effects of anaesthesia, and was enhanced by both tetanization and pairedpulse stimulation. The late (∼20 ms to peak) surface-negative component was generated by a sink in upper layer V and a source deep in layer V, and was greatly enhanced by tetanization and paired-pulse stimulation. The late component did not follow high-frequency stimulation and recovered slowly from anaesthesia, suggesting that it is driven polysynaptically. Potentiation of monosynaptic thalamic and cortico-cortical afferents probably mediates enhancements of the early component and population spikes, while potentiation of polysynaptic afferents to layer V may contribute to growth in the late component. IntroductionLong-term potentiation (LTP) is an activation-induced, longlasting enhancement of synaptic efficacy and is the most widely investigated model of cellular mechanisms of memory (Bliss and Lomo, 1973;Bliss and Collingridge, 1993; Singer, 1995). The neocortex is the putative site for long-term memory storage, but it is relatively resistant to LTP induction. A lthough neocortical LTP can be reliably observed in acute (Wilson and Racine, 1983;Iriki et al., 1991;Racine et al., 1994b; see also Baryani et al., 1991) and in vitro (Artola et al., 1990;Kirkwood et al., 1993;Aroniadou and Keller, 1995; CastroAlamancos et al., 1995;Hess et al., 1996) preparations, it usually requires the use of young animals (Wilson and Racine, 1983;Baskys et al., 1990;Kato et al., 1991) or pharmacological reduction of GA BAergic inhibition (Artola and Singer, 1987; Bindman et al., 1988;Hess and Donoghue, 1994;Kirkwood and Bear, 1994). The adult neocortex in chronic (unanaesthetized) preparations is even more resistant to LTP induction in response to standard tetanization parameters (Racine et al., 1994b). Chronic preparations are required, however, to examine the properties of LTP within the normal milieu of the intact adult brain and to confirm that LTP effects are truly long-lasting.We have recently determined that LTP of neocortical field responses can be reliably induced in chronic preparations when potentiating stimulation trains are spaced and repeated (Racine et al., 1995a,...