Properties and dynamics of inhibitory synaptic communication within the CA3 microcircuits of pyramidal cells and interneurons expressing parvalbumin or cholecystokinin.

KEY POINTS: To understand how a network operates, its elements must be identified and characterized, and the interactions of the elements need to be studied in detail. In the present study, we describe quantitatively the connectivity of two classes of inhibitory neurons in the hippocampal CA3 area (parvalbumin-positive and cholecystokinin-positive interneurons), a key region for the generation of behaviourally relevant synchronous activity patterns. We describe how interactions among these inhibitory cells and their local excitatory target neurons evolve over the course of physiological and pathological activity patterns. The results of the present study enable the construction of precise neuronal network models that may help us understand how network dynamics is generated and how it can underlie information processing and pathological conditions in the brain. We show how inhibitory dynamics between parvalbumin-positive basket cells and pyramidal cells could contribute to sharp wave-ripple generation. ABSTRACT: Different hippocampal activity patterns are determined primarily by the interaction of excitatory cells and different types of interneurons. To understand the mechanisms underlying the generation of different network dynamics, the properties of synaptic transmission need to be uncovered. Perisomatic inhibition is critical for the generation of sharp wave-ripples, gamma oscillations and pathological epileptic activities. Therefore, we aimed to quantitatively and systematically characterize the temporal properties of the synaptic transmission between perisomatic inhibitory neurons and pyramidal cells in the CA3 area of mouse hippocampal slices, using action potential patterns recorded during physiological and pathological network states. Parvalbumin-positive (PV+) and cholecystokinin-positive (CCK+) interneurons showed distinct intrinsic physiological features. Interneurons of the same type formed reciprocally connected subnetworks, whereas the connectivity between interneuron classes was sparse. The characteristics of unitary interactions depended on the identity of both synaptic partners, whereas the short-term plasticity of synaptic transmission depended mainly on the presynaptic cell type. PV+ interneurons showed frequency-dependent depression, whereas more complex dynamics characterized the output of CCK+ interneurons. We quantitatively captured the dynamics of transmission at these different types of connection with simple mathematical models, and describe in detail the response to physiological and pathological discharge patterns. Our data suggest that the temporal propeties of PV+ interneuron transmission may contribute to sharp wave-ripple generation. These findings support the view that intrinsic and synaptic features of PV+ cells make them ideally suited for the generation of physiological network oscillations, whereas CCK+ cells implement a more subtle, graded control in the hippocampus.

Progesterone-dependent immunomodulation.

The biological effects of progesterone are mediated by a 34-kDa protein named the progesterone-induced blocking factor (PIBF). PIBF, synthesized by lymphocytes of healthy pregnant women in the presence of progesterone, inhibits arachidonic acid release as well as NK activity, and modifies the cytokine balance. Within the cell the full-length PIBF is associated with the centrosome, while secretion of shorter forms is induced by activation of the cell. PIBF induces nuclear translocation of STAT6 as well as PKC phosphorylation and exerts a negative effect on STAT4 phosphorylation. The concentration of PIBF in pregnancy urine is related to the positive or negative outcome of pregnancy; furthermore, premature pregnancy termination is predictable by lower than normal pregnancy PIBF values. In vivo data suggest the biological importance of the above findings. Treatment of pregnant Balb/c mice with the antiprogesterone RU 486 results in an increased resorption rate, which is associated with the inability of spleen cells to produce PIBF. High resorption rates induced by progesterone receptor block as well as those due to high NK activity are corrected by simultaneous PIBF treatment.

Distinct isoforms of the cofactor BAG-1 differentially affect Hsc70 chaperone function.

In the mammalian cytosol and nucleus the activity of the molecular chaperone Hsc70 is regulated by chaperone cofactors that modulate ATP binding and hydrolysis by Hsc70. Among such cofactors is the anti-apoptotic protein BAG-1. Remarkably, BAG-1 is expressed as multiple isoforms, which are distinguished by their amino termini. We investigated whether distinct isoforms differ with respect to their Hsc70-regulating activity. By comparing the mainly cytosolic isoforms BAG-1M and BAG-1S, opposite effects of the two isoforms were observed in chaperone-assisted folding reactions. Whereas BAG-1M was found to inhibit the Hsc70-mediated refolding of nonnative polypeptide substrates, the BAG-1S isoform stimulated Hsc70 chaperone activity. The opposite effects are not due to differences in the regulation of the ATPase activity of Hsc70 by the two isoforms. Both isoforms stimulated ATP hydrolysis by Hsc70 in an Hsp40-dependent manner through an acceleration of ADP-ATP exchange. Our results reveal that the different amino termini of the distinct BAG-1 isoforms determine the outcome of an Hsc70-mediated folding event, most likely by transiently interacting with the polypeptide substrate. Employing isoforms of a cofactor with different substrate binding properties appears to provide the means to influence the chaperone function of Hsc70 in addition to modulating its ATPase cycle.

[Chromatographic purity tests of various phenothiazine derivatives. I. Thin-layer chromatography]. / Egyes fenotiazin vázas vegyületek kromatográfiás tisztaságvizsgálata. I. Vékonyrétegkromatográfiás vizsgálatok.

Chromatographic purity tests of four phenothiazine derivatives chlorpromazine, levomepromazine, promethazine and trifluoperazine have been developed. The adsorptive and partition methods are suitable to the separation of the above substances and intermediates as well as side products of their productions. The most common impurities of final products were detected by qualitative purity tests. Densitometric quantitative determinations were carried out on silicagel layer using the solvent system cyclohexanebenzene-diethylamine. Quantity of intermediate impurities were 0.15-0.96%.

[Chromatographic purity tests of various phenothiazine derivatives. II. Gas chromatography]. / Egyes fenotiazin vázas vegyületek kromatográfiás tisztaságvizsgálata. II. Gázkromatográfiás vizsgálatok.

Gas chromatographic purity tests of four phenothiazine derivatives chloropromazine, levomepromazine, promethazine and trifluoperazine have been described. Chromatographic system has been optimized that is suitable to the separation of the above substances and their intermediates as well as their side products. Thermostabilities of phenothiazine derivatives were determined, their thermal decompositions were investigated under gas chromatographic circumstances and the data obtained were completed with data of their thermoanalytical tests. Optimal conditions have been worked out and by applying them thermal decomposition of compounds could be minimized. Authors have drawn attention to formation of artificial products which could not be avoided therefore taking into account requirements of purity tests the application of the method is problematical.