Many cortical synapses exhibit spike timing-dependent plasticity (STDP) in which the precise timing of presynaptic and postsynaptic spikes induces synaptic strengthening [long-term potentiation (LTP)] or weakening [long-term depression (LTD)]. Standard models posit a single, postsynaptic, NMDA receptor-based coincidence detector for LTP and LTD components of STDP. We show instead that STDP at layer 4 to layer 2/3 synapses in somatosensory (S1) cortex involves separate calcium sources and coincidence detection mechanisms for LTP and LTD. LTP showed classical NMDA receptor dependence. LTD was independent of postsynaptic NMDA receptors and instead required group I metabotropic glutamate receptors and calcium from voltage-sensitive channels and IP 3 receptor-gated stores. Downstream of postsynaptic calcium, LTD required retrograde endocannabinoid signaling, leading to presynaptic LTD expression, and also required activation of apparently presynaptic NMDA receptors. These LTP and LTD mechanisms detected firing coincidence on ϳ25 and ϳ125 ms time scales, respectively, and combined to implement the overall STDP rule. These findings indicate that STDP is not a unitary process and suggest that endocannabinoid-dependent LTD may be relevant to cortical map plasticity.

Whisker deprivation weakens excitatory layer 4 (L4) inputs to L2/3 pyramidal cells in rat primary somatosensory (S1) cortex, which is likely to contribute to whisker map plasticity. This weakening has been proposed to represent long-term depression (LTD) induced by sensory deprivation in vivo. Here, we studied the synaptic expression mechanisms for deprivation-induced weakening of L4-L2/3 inputs and assessed its similarity to LTD, which is known to be expressed presynaptically at L4-L2/3 synapses. Whisker deprivation increased the paired pulse ratio at L4-L2/3 synapses and slowed the use-dependent block of NMDA receptor currents by MK-801 [(5S,10R)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], indicating that deprivation reduced transmitter release probability at these synapses. In contrast, deprivation did not alter either miniature EPSC amplitude in L2/3 neurons or the amplitude of quantal L4-L2/3 synaptic responses measured in strontium, indicating that postsynaptic responsiveness was unchanged. In young postnatal day 12 (P12) rats, at least 4 d of deprivation were required to significantly weaken L4-L2/3 synapses. Similar weakening occurred when deprivation began at older ages (P20), when synapses are mostly mature, indicating that weakening is unlikely to represent a failure of synaptic maturation but instead represents a reduction in the strength of existing synapses. Thus, whisker deprivation weakens L4-L2/3 synapses by decreasing presynaptic function, similar to known LTD mechanisms at this synapse.

At a number of synapses, long-term potentiation (LTP) can be expressed by an increase in presynaptic strength, but it is unknown whether presynapticLTPisexpressedsolelythroughanincreaseintheprobabilitythatasinglevesicleisreleasedorwhetheritcanincreasemultivesicular release (MVR). Here, we show that presynaptic LTP decreases inhibition of AMPA receptor EPSCs by a low-affinity antagonist at parallel fiber-molecular layer interneuron (PF-MLI) synapses. This indicates that LTP induction results in larger glutamate concentration transients in the synaptic cleft, a result indicative of MVR, and suggests that MVR can be modified by long-term plasticity. A similar decrease in inhibition was observed when release probability (P R ) was increased by forskolin, elevated extracellular Ca 2ϩ , and paired-pulse facilitation. Furthermore, we show that MVR may occur under baseline physiological conditions, as inhibition increased when P R was lowered by reducing extracellular Ca 2ϩ or by activating presynaptic adenosine receptors. These results suggest that at PF-MLI synapses, MVR occurs under control conditions and is increased when P R is elevated by both short-and long-term plasticity mechanisms.

Endocannabinoids are powerful modulators of synaptic transmission that act on presynaptic cannabinoid receptors. Cannabinoid receptor type 1 (CB1) is the dominant receptor in the CNS, and is present in many brain regions, including sensory cortex. To investigate the potential role of CB1 receptors in cortical development, we examined the developmental expression of CB1 in rodent primary somatosensory (barrel) cortex, using immunohistochemistry with a CB1-specific antibody. We found that before postnatal day (P) 6, CB1 receptor staining was present exclusively in the cortical white matter, and that CB1 staining appeared in the grey matter between P6 and P20 in a specific laminar pattern. CB1 staining was confined to axons, and was most prominent in cortical layers 2/3, 5a, and 6. CB1 null (−/−) mice showed altered anatomical barrel maps in layer 4, with enlarged interbarrel septa, but normal barrel size. These results indicate that CB1 receptors are present in early postnatal development and influence development of sensory maps. KeywordsCannabinoid; whisker; barrel; septa; axons; sensory map The endocannabinoid (eCB) signaling system modulates synaptic transmission in many brain areas, including striatum, cerebellum, hippocampus, and neocortex (Chevaleyre et al., 2006). eCBs are lipids that are synthesized by postsynaptic neurons in response to depolarization, increases in intracellular calcium, and/or activation of specific metabotropic neurotransmitter receptors. eCBs diffuse retrogradely to activate cannabinoid receptors on presynaptic terminals, with the CB1 receptor being the primary cannabinoid receptor on presynaptic terminals in the brain (Piomelli et al., 1998; Nicoll, 2001, 2002;Freund et al., 2003). CB1 receptors occur most prominently on inhibitory terminals (Marsicano and Lutz, 1999;Bodor et al., 2005), but also exist on excitatory terminals (Katona et al., 2006;Kawamura et al., 2006;Monory et al., 2006). CB1 receptor activation reduces presynaptic release 4 Corresponding author: phone 858-822-4271, fax 858-534-7309, dfeldman@ucsd.edu. * These authors contributed equally to this work.Section Editor: Chip Gerfen, Neuroanatomy.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brown et al., 2004), leading to short-term and long-term depression of excitatory and inhibitory transmission (Wilson and Nicoll, 2002;Chevaleyre et al., 2006). Such CB1-mediated synaptic plasticity is prominent in mature and adolescent neocortex (Sjostrom et al., 2003;Trettel and Levine, 2003;Trettel et al., 2004;Bodor et al., 2005;Bender et al., 2006b;Domenici et al., 2006). NIH ...

Backpropagating action potentials (bAPs) are an important signal for associative synaptic plasticity in many neurons, but they often fail to fully invade distal dendrites. In this issue of Neuron, Sjöström and Häusser show that distal propagation failure leads to a spatial gradient of Hebbian plasticity in neocortical pyramidal cells. This gradient can be overcome by cooperative distal synaptic input, leading to fundamentally distinct Hebbian learning rules for distal versus proximal synapses.