@article{1616, abstract = {The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3–6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input-output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation.}, author = {Kowalski, Janina and Gan, Jian and Jonas, Peter M and Pernia-Andrade, Alejandro}, issn = {1098-1063}, journal = {Hippocampus}, number = {5}, pages = {668 -- 682}, publisher = {Wiley}, title = {{Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats}}, doi = {10.1002/hipo.22550}, volume = {26}, year = {2016}, } @article{1535, abstract = {Neuronal and neuroendocrine L-type calcium channels (Cav1.2, Cav1.3) open readily at relatively low membrane potentials and allow Ca2+ to enter the cells near resting potentials. In this way, Cav1.2 and Cav1.3 shape the action potential waveform, contribute to gene expression, synaptic plasticity, neuronal differentiation, hormone secretion and pacemaker activity. In the chromaffin cells (CCs) of the adrenal medulla, Cav1.3 is highly expressed and is shown to support most of the pacemaking current that sustains action potential (AP) firings and part of the catecholamine secretion. Cav1.3 forms Ca2+-nanodomains with the fast inactivating BK channels and drives the resting SK currents. These latter set the inter-spike interval duration between consecutive spikes during spontaneous firing and the rate of spike adaptation during sustained depolarizations. Cav1.3 plays also a primary role in the switch from “tonic” to “burst” firing that occurs in mouse CCs when either the availability of voltage-gated Na channels (Nav) is reduced or the β2 subunit featuring the fast inactivating BK channels is deleted. Here, we discuss the functional role of these “neuronlike” firing modes in CCs and how Cav1.3 contributes to them. The open issue is to understand how these novel firing patterns are adapted to regulate the quantity of circulating catecholamines during resting condition or in response to acute and chronic stress.}, author = {Vandael, David H and Marcantoni, Andrea and Carbone, Emilio}, journal = {Current Molecular Pharmacology}, number = {2}, pages = {149 -- 161}, publisher = {Bentham Science Publishers}, title = {{Cav1.3 channels as key regulators of neuron-like firings and catecholamine release in chromaffin cells}}, doi = {10.2174/1874467208666150507105443}, volume = {8}, year = {2015}, } @article{1565, abstract = {Leptin is an adipokine produced by the adipose tissue regulating body weight through its appetite-suppressing effect. Besides being expressed in the hypothalamus and hippocampus, leptin receptors (ObRs) are also present in chromaffin cells of the adrenal medulla. In the present study, we report the effect of leptin on mouse chromaffin cell (MCC) functionality, focusing on cell excitability and catecholamine secretion. Acute application of leptin (1 nm) on spontaneously firing MCCs caused a slowly developing membrane hyperpolarization followed by complete blockade of action potential (AP) firing. This inhibitory effect at rest was abolished by the BK channel blocker paxilline (1 μm), suggesting the involvement of BK potassium channels. Single-channel recordings in 'perforated microvesicles' confirmed that leptin increased BK channel open probability without altering its unitary conductance. BK channel up-regulation was associated with the phosphoinositide 3-kinase (PI3K) signalling cascade because the PI3K specific inhibitor wortmannin (100 nm) fully prevented BK current increase. We also tested the effect of leptin on evoked AP firing and Ca2+-driven exocytosis. Although leptin preserves well-adapted AP trains of lower frequency, APs are broader and depolarization-evoked exocytosis is increased as a result of the larger size of the ready-releasable pool and higher frequency of vesicle release. The kinetics and quantal size of single secretory events remained unaltered. Leptin had no effect on firing and secretion in db-/db- mice lacking the ObR gene, confirming its specificity. In conclusion, leptin exhibits a dual action on MCC activity. It dampens AP firing at rest but preserves AP firing and increases catecholamine secretion during sustained stimulation, highlighting the importance of the adipo-adrenal axis in the leptin-mediated increase of sympathetic tone and catecholamine release.}, author = {Gavello, Daniela and Vandael, David H and Gosso, Sara and Carbone, Emilio and Carabelli, Valentina}, journal = {Journal of Physiology}, number = {22}, pages = {4835 -- 4853}, publisher = {Wiley-Blackwell}, title = {{Dual action of leptin on rest-firing and stimulated catecholamine release via phosphoinositide 3-kinase-riven BK channel up-regulation in mouse chromaffin cells}}, doi = {10.1113/JP271078}, volume = {593}, year = {2015}, } @article{1580, abstract = {Synapsins (Syns) are an evolutionarily conserved family of presynaptic proteins crucial for the fine-tuning of synaptic function. A large amount of experimental evidences has shown that Syns are involved in the development of epileptic phenotypes and several mutations in Syn genes have been associated with epilepsy in humans and animal models. Syn mutations induce alterations in circuitry and neurotransmitter release, differentially affecting excitatory and inhibitory synapses, thus causing an excitation/inhibition imbalance in network excitability toward hyperexcitability that may be a determinant with regard to the development of epilepsy. Another approach to investigate epileptogenic mechanisms is to understand how silencing Syn affects the cellular behavior of single neurons and is associated with the hyperexcitable phenotypes observed in epilepsy. Here, we examined the functional effects of antisense-RNA inhibition of Syn expression on individually identified and isolated serotonergic cells of the Helix land snail. We found that Helix synapsin silencing increases cell excitability characterized by a slightly depolarized resting membrane potential, decreases the rheobase, reduces the threshold for action potential (AP) firing and increases the mean and instantaneous firing rates, with respect to control cells. The observed increase of Ca2+ and BK currents in Syn-silenced cells seems to be related to changes in the shape of the AP waveform. These currents sustain the faster spiking in Syn-deficient cells by increasing the after hyperpolarization and limiting the Na+ and Ca2+ channel inactivation during repetitive firing. This in turn speeds up the depolarization phase by reaching the AP threshold faster. Our results provide evidence that Syn silencing increases intrinsic cell excitability associated with increased Ca2+ and Ca2+-dependent BK currents in the absence of excitatory or inhibitory inputs.}, author = {Brenes, Oscar and Vandael, David H and Carbone, Emilio and Montarolo, Pier and Ghirardi, Mirella}, journal = {Neuroscience}, pages = {430 -- 443}, publisher = {Elsevier}, title = {{Knock-down of synapsin alters cell excitability and action potential waveform by potentiating BK and voltage gated Ca2 currents in Helix serotonergic neurons}}, doi = {10.1016/j.neuroscience.2015.10.046}, volume = {311}, year = {2015}, } @article{1615, abstract = {Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.}, author = {Hammer, Matthieu and Krueger Burg, Dilja and Tuffy, Liam and Cooper, Benjamin and Taschenberger, Holger and Goswami, Sarit and Ehrenreich, Hannelore and Jonas, Peter M and Varoqueaux, Frederique and Rhee, Jeong and Brose, Nils}, journal = {Cell Reports}, number = {3}, pages = {516 -- 523}, publisher = {Cell Press}, title = {{Perturbed hippocampal synaptic inhibition and γ-oscillations in a neuroligin-4 knockout mouse model of autism}}, doi = {10.1016/j.celrep.2015.09.011}, volume = {13}, year = {2015}, } @article{1614, abstract = {GABAergic perisoma-inhibiting fast-spiking interneurons (PIIs) effectively control the activity of large neuron populations by their wide axonal arborizations. It is generally assumed that the output of one PII to its target cells is strong and rapid. Here, we show that, unexpectedly, both strength and time course of PII-mediated perisomatic inhibition change with distance between synaptically connected partners in the rodent hippocampus. Synaptic signals become weaker due to lower contact numbers and decay more slowly with distance, very likely resulting from changes in GABAA receptor subunit composition. When distance-dependent synaptic inhibition is introduced to a rhythmically active neuronal network model, randomly driven principal cell assemblies are strongly synchronized by the PIIs, leading to higher precision in principal cell spike times than in a network with uniform synaptic inhibition. }, author = {Strüber, Michael and Jonas, Peter M and Bartos, Marlene}, journal = {PNAS}, number = {4}, pages = {1220 -- 1225}, publisher = {National Academy of Sciences}, title = {{Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells}}, doi = {10.1073/pnas.1412996112}, volume = {112}, year = {2015}, } @article{1845, abstract = {Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression. Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression.}, author = {Vandael, David H and Espinoza Martinez, Claudia and Jonas, Peter M}, journal = {Neuron}, number = {6}, pages = {1149 -- 1151}, publisher = {Elsevier}, title = {{Excitement about inhibitory presynaptic terminals}}, doi = {10.1016/j.neuron.2015.03.006}, volume = {85}, year = {2015}, } @article{1834, abstract = {Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.}, author = {Chen, Chong and Wang, Chao and Zhao, Xuan and Zhou, Tao and Xu, Dao and Wang, Zhi and Wang, Ying}, journal = {ASN Neuro}, number = {2}, publisher = {SAGE Publications}, title = {{Low-dose sevoflurane promoteshippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats}}, doi = {10.1177/1759091415575845}, volume = {7}, year = {2015}, } @article{1890, abstract = {To search for a target in a complex environment is an everyday behavior that ends with finding the target. When we search for two identical targets, however, we must continue the search after finding the first target and memorize its location. We used fixation-related potentials to investigate the neural correlates of different stages of the search, that is, before and after finding the first target. Having found the first target influenced subsequent distractor processing. Compared to distractor fixations before the first target fixation, a negative shift was observed for three subsequent distractor fixations. These results suggest that processing a target in continued search modulates the brain's response, either transiently by reflecting temporary working memory processes or permanently by reflecting working memory retention.}, author = {Körner, Christof and Braunstein, Verena and Stangl, Matthias and Schlögl, Alois and Neuper, Christa and Ischebeck, Anja}, journal = {Psychophysiology}, number = {4}, pages = {385 -- 395}, publisher = {Wiley-Blackwell}, title = {{Sequential effects in continued visual search: Using fixation-related potentials to compare distractor processing before and after target detection}}, doi = {10.1111/psyp.12062}, volume = {51}, year = {2014}, } @article{2002, abstract = {Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outsideout patch recordings from CA1 pyramidal neuron axons revealed a high density of a-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.}, author = {Kim, Sooyun}, journal = {PLoS One}, number = {11}, publisher = {Public Library of Science}, title = {{Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus}}, doi = {10.1371/journal.pone.0113124}, volume = {9}, year = {2014}, }