Proline-catalysed asymmetric ketol cyclizations: the template mechanism revisited

A modified template mechanism based on modelling studies of energy minimised complexes is presented for the asymmetric proline-catalysed cyclization of triketones1,2 and3 to the 2S,3S-ketols1a,2a and3a respectively. The template model involves a three-point contact as favoured in enzyme-substrate interactions. Our minimisation studies are in agreement with the divergent behaviour of the 6,5-, 6,6-and 6,7-bicyclic systems. They support the high 93.4%ee observed with the 6,5-bicyclic ketol and the lower 73%ee found with the 6,6-bicyclic ketol. The calculations also explain the lack of asymmetric induction with the 6,7-bicyclic system

Nitric Oxide Signaling Modulates Synaptic Transmission during Early Postnatal Development

Early γ-aminobutyric acid mediated (GABAergic) synaptic transmission and correlated neuronal activity are fundamental to network formation; however, their regulation during early postnatal development is poorly understood. Nitric oxide (NO) is an important retrograde messenger at glutamatergic synapses, and it was recently shown to play an important role also at GABAergic synapses in the adult brain. The subcellular localization and network effect of this signaling pathway during early development are so far unexplored, but its disruption at this early age is known to lead to profound morphological and functional alterations. Here, we provide functional evidence—using whole-cell recording—that NO signaling modulates not only glutamatergic but also GABAergic synaptic transmission in the mouse hippocampus during the early postnatal period. We identified the precise subcellular localization of key elements of the underlying molecular cascade using immunohistochemistry at the light—and electron microscopic levels. As predicted by these morpho-functional data, multineuron calcium imaging in acute slices revealed that this NO-signaling machinery is involved also in the control of synchronous network activity patterns. We suggest that the retrograde NO-signaling system is ideally suited to fulfill a general presynaptic regulatory role and may effectively fine-tune network activity during early postnatal development, while GABAergic transmission is still depolarizing

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Synthetic Culture Media Evaluated for the Detection of Coliform Bacteria in Milk, Cheese and Egg Melange

Simple synthetic culture media of liquid and solid form (X broth and X agar) were tested for selective isolation of coliform bacteria. Selectivity is based on the ability of coliform bacteria to grow when the minimal medium contains simple inorganic substances as nitrogen and carbon supply. Selectivity of the media was tested by inoculation of pure cultures of different microbes belonging to the genera of Staphylococcus, Bacillus and Pseudomonas and the family Enterobacteriaceae and was found to be complete in this range. The comparative investigation of milk, camembert cheese and egg melange samples in the traditional and new media proved good applicability of X broth and X agar for an effective and selective detection of coliform bacteria. When testing pasteurized milk samples, X agar detected coliforms in significantly higher counts than violet red-bile-lactose agar

The effects of interactions between proline and carbon nanostructures on organocatalysis in the Hajos-Parrish-Eder-Sauer-Wiechert reaction

The non-covalent interactions of S-(-)-proline with the surfaces of carbon nanostructures (fullerene, nanotubes and graphite) change the nucleophilic-electrophilic and acid-base properties of the amino acid, thus tuning its activity and selectivity in the organocatalytic Hajos-Parrish-Eder-Sauer-Wiechert (HPESW) reaction. Whilst our spectroscopy and microscopy measurements show no permanent covalent bonding between S-(-)-proline and carbon nanostructures, a systematic investigation of the catalytic activity and selectivity of the organocatalyst in the HPESW reaction demonstrates a clear correlation between the pyramidalisation angle of carbon nanostructures and the catalytic properties of S-(-)-proline. Carbon nanostructures with larger pyramidalisation angles have a stronger interaction with the nitrogen atom lone pair of electrons of the organocatalyst, thereby simultaneously decreasing the nucleophilicity and increasing the acidity of the organocatalyst. These translate into lower conversion rates but higher selectivities towards the dehydrated product of Aldol addition

Cannabinoid-mediated short-term plasticity in hippocampus

Endocannabinoids modulate both excitatory and inhibitory neurotransmission in hippocampus via activation of pre-synaptic cannabinoid receptors. Here, we present a model for cannabinoid mediated short-term depression of excitation (DSE) based on our recently developed model for the equivalent phenomenon of suppressing inhibition (DSI). Furthermore, we derive a simplified formulation of the calcium-mediated endocannabinoid synthesis that underlies short-term modulation of neurotransmission in hippocampus. The simplified model describes cannabinoid-mediated short-term modulation of both hippocampal inhibition and excitation and is ideally suited for large network studies. Moreover, the implementation of the simplified DSI/DSE model provides predictions on how both phenomena are modulated by the magnitude of the pre-synaptic cell's activity. In addition we demonstrate the role of DSE in shaping the post-synaptic cell's firing behaviour qualitatively and quantitatively in dependence on eCB availability and the pre-synaptic cell's activity. Finally, we explore under which conditions the combination of DSI and DSE can temporarily shift the fine balance between excitation and inhibition. This highlights a mechanism by which eCBs might act in a neuro-protective manner during high neural activity

The effects of acute serotonin challenge on executive planning in patients with obsessive-compulsive disorder (OCD), their first-degree relatives, and healthy controls

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00213-020-05597-7.Rationale: OCD is characterized by executive function impairment and by clinical responsivity to selective serotonin reuptake inhibitors (SSRIs). Executive planning deficits constitute a candidate endophenotype for OCD. It is not known whether this endophenotype is responsive to acute serotonin manipulation. Objective: To investigate the effects of acute SSRI administration on executive function in patients with OCD, first-degree relatives of patients with OCD and healthy controls. Methods: A randomized double-blind crossover study assessed the effects of single dose escitalopram (20mg) and placebo on executive planning in 24 patients with OCD, 13 clinically unaffected first-degree relatives of patients with OCD and 28 healthy controls. Performance on a Tower of London task measuring executive planning was assessed 4 hours after oral administration of the pharmacological challenge / placebo, and compared across and within groups using a mixed model ANOVA. Results: On the outcome measure of interest, i.e. the mean number of choices to obtain the correct solution, there was a marginally significant effect of group (F(2, 59)=3.1; p=0.052), with patients (Least square [LS] mean: 1.43; Standard Error [SE]: 0.06; 95% confidence interval [CI], 1.31-1.55) and their relatives (LS mean: 1.46; SE: 0.08; 95% CI, 1.30-1.62) performing worse than matched healthy controls (LS mean: 1.26; SE: 0.05; 95% CI, 1.15-1.37) on placebo. There was a trend towards a significant group x treatment interaction (F(2, 58)=2.8, p=0.069), with post hoc tests showing (i) patients (p=0.009; LS mean difference: 0.23; SE: 0.08) and relatives (p=0.03; LS mean difference: 0.22; SE: 0.10) were more impaired compared to controls and (ii) escitalopram was associated with improved executive planning in patients with OCD (p=0.013; LS mean difference: 0.1; SE: 0.04), but not other groups (both p>0.1; controls: LS mean difference: -0.03; SE: 0.04; relatives: LS mean difference: 0.02; SE: 0.05). Conclusion: Our findings are consistent with a view that there is impaired executive planning in OCD, and that this constitutes a behavioral endophenotype. In patients with OCD, but not in relatives, acute SSRI administration ameliorated this deficit. Further investigation is needed to understand common and differential involvement of neurochemical systems in patients with OCD and their relatives.Peer reviewe

Encoding of Naturalistic Stimuli by Local Field Potential Spectra in Networks of Excitatory and Inhibitory Neurons

Recordings of local field potentials (LFPs) reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory–excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus–neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment

Fast Homeostatic Plasticity of Inhibition via Activity-Dependent Vesicular Filling

Synaptic activity in the central nervous system undergoes rapid state-dependent changes, requiring constant adaptation of the homeostasis between excitation and inhibition. The underlying mechanisms are, however, largely unclear. Chronic changes in network activity result in enhanced production of the inhibitory transmitter GABA, indicating that presynaptic GABA content is a variable parameter for homeostatic plasticity. Here we tested whether such changes in inhibitory transmitter content do also occur at the fast time scale required to ensure inhibition-excitation-homeostasis in dynamic cortical networks. We found that intense stimulation of afferent fibers in the CA1 region of mouse hippocampal slices yielded a rapid and lasting increase in quantal size of miniature inhibitory postsynaptic currents. This potentiation was mediated by the uptake of GABA and glutamate into presynaptic endings of inhibitory interneurons (the latter serving as precursor for the synthesis of GABA). Thus, enhanced release of inhibitory and excitatory transmitters from active networks leads to enhanced presynaptic GABA content. Thereby, inhibitory efficacy follows local neuronal activity, constituting a negative feedback loop and providing a mechanism for rapid homeostatic scaling in cortical circuits

Reduced neural synchronization of gamma-band MEG oscillations in first-degree relatives of children with autism

<p>Abstract</p> <p>Background</p> <p>Gamma-band oscillations recorded from human electrophysiological recordings, which may be associated with perceptual binding and neuronal connectivity, have been shown to be altered in people with autism. Transient auditory gamma-band responses, however, have not yet been investigated in autism or in the first-degree relatives of persons with the autism.</p> <p>Methods</p> <p>We measured transient evoked and induced magnetic gamma-band power and inter-trial phase-locking consistency in the magnetoencephalographic recordings of 16 parents of children with autism, 11 adults with autism and 16 control participants. Source space projection was used to separate left and right hemisphere transient gamma-band measures of power and phase-locking.</p> <p>Results</p> <p>Induced gamma-power at 40 Hz was significantly higher in the parent and autism groups than in controls, while evoked gamma-band power was reduced compared to controls. The phase-locking factor, a measure of phase consistency of neuronal responses with external stimuli, was significantly lower in the subjects with autism and the autism parent group, potentially explaining the difference between the evoked and induced power results.</p> <p>Conclusion</p> <p>These findings, especially in first degree relatives, suggest that gamma-band phase consistency and changes in induced versus induced power may be potentially useful endophenotypes for autism, particularly given emerging molecular mechanisms concerning the generation of gamma-band signals.</p