Frequency-Dependent Cannabinoid Receptor-Independent Modulation of Glycine Receptors by Endocannabinoid 2-AG

Endocannabinoids are known as retrograde messengers, being released from the postsynaptic neuron and acting on specific presynaptic G-protein-coupled cannabinoid (CB) receptors to decrease neurotransmitter release. Also, at physiologically relevant concentrations cannabinoids can directly modulate the function of voltage-gated and receptor-operated ion channels. Using patch-clamp recording we analyzed the consequences of the direct action of an endocannabinoid, 2-arachidonoylglycerol (2-AG), on the functional properties of glycine receptor channels (GlyRs) and ionic currents in glycinergic synapses. At physiologically relevant concentrations (0.1–1 μM), 2-AG directly affected the functions of recombinant homomeric α1H GlyR: it inhibited peak amplitude and dramatically enhanced desensitization. The action of 2-AG on GlyR-mediated currents developed rapidly, within ∼300 ms. Addition of 1 μM 2-AG strongly facilitated the depression of glycine-induced currents during repetitive (4–10 Hz) application of short (2 ms duration) pulses of glycine to outside-out patches. In brainstem slices from CB1 receptor knockout mice, 2-AG significantly decreased the extent of facilitation of synaptic currents in hypoglossal motoneurons during repetitive (10–20 Hz) stimulation. These observations suggest that endocannabinoids can modulate postsynaptic metaplasticity of glycinergic synaptic currents in a CB1 receptor-independent manner

Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?

The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl–)I) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl–)I with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl–)I levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease

Animal Intelligence

So far as evolution is concerned, it really matters little\u27 at what point intelligence appears. Intelligence proper includes the reasoning power as its chief and distinguishing characteristic. Facts regarded as proving a degree of this power in animals were reviewed in detail, and shown to be susceptible of a lower interpretation in harmony with the general phenomena of animal life

Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons.Weinvestigated whether similar signatures are present in Pink1-/- mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1-/-mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1-/- mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1-/- mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1-/-mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1-/- mic

Approaches to management and digital hardware support of business processes of food facilities

The food industry is included in the process industries and is a strategically important sector of the Russian market economy, associated with processing, storage, distribution and marketing of products to consumers. The business processes of the studied industry are a form of communication and technological interaction of personnel to achieve the goals and objectives in the organization. In this industry with existing business models corresponding to their size, have different conditions for doing business, technical support for raw materials processing and the release of final products, availability or shortage of qualified personnel, different level, forms of support from state and municipal authorities. Building a process-oriented enterprise management structure concerns many traditional management approaches, however, many researchers suggest that with the development of digital economy technologies, many achievements of the scientific organization of work of domestic and foreign scientists. It should also be noted that any equipment has its own period of use, and many food industry enterprises in the Russian Federation have depreciation of production assets (more than 40%), unprofitability, insufficient support from regional and municipal authorities. As a result of these characteristics, the issue of ensuring the profitability of processing and marketing products, as well as ensuring that the needs of consumers are satisfied not only in the immediate environment, but also in other segments of the country's market, becomes acute for each head of the organization of the food industry, regardless of the size and form of ownership

Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons.Weinvestigated whether similar signatures are present in Pink1-/- mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1-/-mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1-/- mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1-/- mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1-/-mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1-/- mice. © 2012 the authors.The study was financed by Inserm, Association France-Parkinson (C.H.), ERA-Net Neuron (C.H.), the Deutsche Forschungsgemeinschaft (GI 432/3-1), and the Bundesministerium für Forschung through the National Genome Research Network (NGFNplus).Peer Reviewe