Rhodium-Catalyzed [4+2+1] Cycloaddition of In Situ Generated Ene/Yne-Ene-Allenes and CO.

Reported herein is the first rhodium-catalyzed [4+2+1] cycloaddition of in situ generated ene/yne-ene-allenes and CO to synthesize challenging seven-membered carbocycles fused with five-membered rings. This reaction is designed based on the 1,3-acyloxy migration of ene/yne-ene-propargyl esters to ene/yne-ene-allenes, followed by oxidative cyclization, CO insertion, and reductive elimination to form the final [4+2+1] cycloadducts. The possible competing [4+1], [4+2], and [2+2+1] cycloadditions were disfavored, making the present reaction an efficient way to access functionalized 5/7 rings.

Rhodium(I)-Catalyzed Bridged [5+2] Cycloaddition of cis-Allene-vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton.

Previously reported was that cis-ene-vinylcyclopropanes (cis-ene-VCPs) underwent Rh-catalyzed [5+2] reaction to give 5,7-fused bicyclic products, where vinylcyclopropane (VCP) acts as five-carbon synthon. Unfortunately, this reaction had very limited scope. Replacing the 2π component of cis-ene-VCPs to allene moiety, the corresponding cis-allene-VCPs did not undergo the expected normal [5+2] cycloaddition to give 5,7-fused bicyclic products. Instead, the challenging bicyclo[4.3.1]decane skeleton was obtained via an unprecedented bridged [5+2] cycloaddition. DFT calculations were applied to understand why this bridged [5+2] reaction is favored over the anticipated but not realized normal [5+2] reaction.

Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: reaction development and application to the formal synthesis of (-)-galanthamine.

A Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO has been developed to synthesize functionalized 2-methylidene-3,4-cyclohexenones. The scope of this methodology has been investigated, showing that various functional groups can be tolerated. Both di- and tri-substituted allenylcyclopropanes can be applied to this cycloaddition and the [5 + 1] cycloadducts with the E configuration were obtained as the major products. In addition, the present [5 + 1] cycloaddition reaction has been utilized as a key step in the formal synthesis of the natural product (-)-galanthamine.

Electrical synapses formed by connexin36 regulate inhibition- and experience-dependent plasticity.

The mammalian brain constantly adapts to new experiences of the environment, and inhibitory circuits play a crucial role in this experience-dependent plasticity. A characteristic feature of inhibitory neurons is the establishment of electrical synapses, but the function of electrical coupling in plasticity is unclear. Here we show that elimination of electrical synapses formed by connexin36 altered inhibitory efficacy and caused frequency facilitation of inhibition consistent with a decreased GABA release in the inhibitory network. The altered inhibitory efficacy was paralleled by a failure of theta-burst long-term potentiation induction and by impaired ocular dominance plasticity in the visual cortex. Together, these data suggest a unique mechanism for regulating plasticity in the visual cortex involving synchronization of inhibitory networks via electrical synapses.

Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation.

A dramatic form of experience-dependent synaptic plasticity is revealed in visual cortex when one eye is temporarily deprived of vision during early postnatal life. Monocular deprivation (MD) alters synaptic transmission such that cortical neurons cease to respond to stimulation of the deprived eye, but how this occurs is poorly understood. Here we show in rat visual cortex that brief MD sets in motion the same molecular and functional changes as the experimental model of homosynaptic long-term depression (LTD), and that prior synaptic depression by MD occludes subsequent induction of LTD. The mechanisms of LTD, about which there is now a detailed understanding, therefore contribute to visual cortical plasticity.

Selective activation of a putative reinforcement signal conditions cued interval timing in primary visual cortex.

As a consequence of conditioning visual cues with delayed reward, cue-evoked neural activity that predicts the time of expected future reward emerges in the primary visual cortex (V1). We hypothesized that this reward-timing activity is engendered by a reinforcement signal conveying reward acquisition to V1. In lieu of behavioral conditioning, we assessed in vivo whether selective activation of either basal forebrain (BF) or cholinergic innervation is sufficient to condition cued interval-timing activity. Substituting for actual reward, optogenetic activation of BF or cholinergic input within V1 at fixed delays following visual stimulation entrains neural responses that mimic behaviorally conditioned reward-timing activity. Optogenetically conditioned neural responses express cue-evoked temporal intervals that correspond to the conditioning intervals, are bidirectionally modifiable, display experience-dependent refinement, and exhibit a scale invariance to the encoded delay. Our results demonstrate that the activation of BF or cholinergic input within V1 is sufficient to encode cued interval-timing activity and indicate that V1 itself is a substrate for associative learning that may inform the timing of visually cued behaviors.

Gold(I)-catalyzed polycyclization of linear dienediynes to seven-membered ring-containing polycycles via tandem cyclopropanation/Cope rearrangement/C-H activation.

A novel gold(I)-catalyzed polycyclization of easily prepared linear dienediynes has been developed for the construction of fused 5,7,6-tricyclic ring systems in one step with high diastereocontrol. The polycyclization, a formal [4 + 3]/C-H activation reaction, takes place through gold(I)-catalyzed intramolecular cyclopropanation of diene with diyne, Cope rearrangement of cis-alkenylalkynylcyclopropane, aliphatic C-H activation via a seven-membered-ring allene intermediate, and [1,2]-H and -G (H or OAc) shifts.

Cannabinoid receptor blockade reveals parallel plasticity mechanisms in different layers of mouse visual cortex.

The ocular dominance (OD) shift that occurs in visual cortex after brief monocular deprivation (MD) is a classic model of experience-dependent cortical plasticity. It has been suggested that OD plasticity in layer 2/3 of visual cortex precedes and is necessary for plasticity in the thalamocortical input layer 4. Here, we show in mouse visual cortex that rapid OD plasticity occurs simultaneously in layers 2/3 and 4. Remarkably, pharmacological blockade of cannabinoid receptors completely prevents the OD shift in layer 2/3, leaving plasticity intact in layer 4. Thus, experience-dependent cortical modifications in layers 2/3 and 4 can occur in parallel, via distinct mechanisms. These findings simplify the mechanistic description of plasticity in layer 4, force a revision in the interpretation of previous studies in which laminar differences in OD plasticity mechanisms were unrecognized, and have important implications for the therapeutic use of cannabinoid receptor antagonists in humans.

Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex.

Long-term depression (LTD) induced by low-frequency synaptic stimulation (LFS) was originally introduced as a model to probe potential mechanisms of deprivation-induced synaptic depression in visual cortex. In hippocampus, LTD requires activation of postsynaptic NMDA receptors, PKA, and the clathrin-dependent endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. It has long been assumed that LTD induced in visual cortical layer 2/3 by LFS of layer 4 uses similar mechanisms. Here we show in mouse visual cortex that this conclusion requires revision. We find that LTD induced in layer 2/3 by LFS is unaffected by inhibitors of PKA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis but is reliably blocked by an endocannabinoid CB1 receptor antagonist. Conversely, LFS applied to synapses on layer 4 neurons produces LTD that appears mechanistically identical to that in CA1 and is insensitive to CB1 blockers. Occlusion experiments suggest that both mechanisms contribute to the loss of visual responsiveness after monocular deprivation.