Anatomically heterogeneous populations of CB cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics

A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that approximately 40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells. (c) 2014 Wiley Periodicals, Inc

Sinteza i cAMP-ovisna inhibicija fosfodiesteraze novih derivata tiazolokinazolina

The series of 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine) thiazolo(2,3-b)quinazolin-3(2H)-ones (4a-j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine)-3-(4-nitrophenylamino)thiazoloquinazolines (5a-j) were synthesized by the reported method and evaluated for their phosphodiesterase inhibitory activity. All test compounds exhibited good activity. The structure-activity relationships were also studied. In both series of compounds, electron-withdrawing substitutions showed higher activity. Among the tested compounds, 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-fluorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5e), 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-nitrobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-chlorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5f) were found to be more potent than theophylline (IC50 in mmol L–1 of 1.34 ± 0.09 for 5f, 1.44 ± 0.02 for 5e, 1.52 ± 0.05 for 5j vs. 1.72 ± 0.09 for theophylline).U radu je opisana sinteza serije 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)tiazolo(2,3-b)kinazolin-3(2H)-ona (4a-j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)-3-(4-nitrofenilamino)tiazolokinazolina (5a-j) prema objavljenoj metodi te ispitano njihovo inhibitorno djelovanje na fosfodiesterazu. Svi testirani spojevi pokazuju dobro djelovanje. Proučavan je i odnos strukture i djelovanja. U obje serije spojeva, elektron-odvlačeći supstituenti doprinose jačem djelovanju. Među ispitivanim spojevima pronađeno je da 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-fluorobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5e), 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-nitrobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-klorobenzilidin)-3-(4-nitrofenilamino)tiazolokinazolin (5f) imaju jače djelovanje od teofilina (IC50 u mmol L–1 1,34 ± 0,09 za 5f, 1,44 ± 0,02 za 5e, 1,52 ± 0,05 za 5j nasuprot 1,72 ± 0,09 za teofilin)

Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo.

Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation

Behavior-dependent specialization of identified hippocampal interneurons.

A large variety of GABAergic interneurons control information processing in the hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information processing during behavior is not known. We employed a new technique for recording and labeling interneurons and pyramidal cells in drug-free, freely moving rats. Recorded parvalbumin-expressing basket interneurons innervated somata and proximal pyramidal cell dendrites, whereas nitric oxide synthase- and neuropeptide Y-expressing ivy cells provided synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike-timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket, but not ivy, cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state-contingent manner, whereas persistently firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thereby differentially controlling network activity during behavior

Behavior-dependent specialization of identified hippocampal interneurons.

A large variety of GABAergic interneurons control information processing in the hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information processing during behavior is not known. We employed a new technique for recording and labeling interneurons and pyramidal cells in drug-free, freely moving rats. Recorded parvalbumin-expressing basket interneurons innervated somata and proximal pyramidal cell dendrites, whereas nitric oxide synthase- and neuropeptide Y-expressing ivy cells provided synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike-timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket, but not ivy, cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state-contingent manner, whereas persistently firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thereby differentially controlling network activity during behavior

Navigating the circuitry of the brain's GPS system: future challenges for neurophysiologists

The discovery of the brain's navigation system creates a compelling challenge for neurophysiologists: how do we map the circuitry of a system that can only be definitively identified in awake, behaving animals? Do grid and border cells in the entorhinal cortex correspond to the two classes of principal cell found there, stellate and pyramidal cells? In the hippocampus, does the diversity seen in pyramidal cell subtypes have functional correlates in the place cell system? How do interneurons regulate the activity of spatially tuned principal cells in the hippocampal and entorhinal circuits? Here, we discuss recent literature relating the cellular circuitry of these circuits to in vivo studies of the brain's navigation system, and the role that interneurons have in regulating the activity of principal cells in these circuits. We propose that studying in vitro models of neuronal oscillations in the entorhinal cortex and hippocampus can provide useful insights for bridging the gap in understanding that exists in relating in vivo and behavioral studies to circuit function at the cellular level