Ca(2+)-activated Cl(-) currents are dispensable for olfaction

Canonical olfactory signal transduction involves the activation of cyclic AMP-activated cation channels that depolarize the cilia of receptor neurons and raise intracellular calcium. Calcium then activates Cl(-) currents that may be up to tenfold larger than cation currents and are believed to powerfully amplify the response. We identified Anoctamin2 (Ano2, also known as TMEM16B) as the ciliary Ca(2+)-activated Cl(-) channel of olfactory receptor neurons. Ano2 is expressed in the main olfactory epithelium (MOE) and in the vomeronasal organ (VNO), which also expresses the related Ano1 channel. Disruption of Ano2 in mice virtually abolished Ca(2+)-activated Cl(-) currents in the MOE and VNO. Ano2 disruption reduced fluid-phase electro-olfactogram responses by only approximately 40%, did not change air-phase electro-olfactograms and did not reduce performance in olfactory behavioral tasks. In contrast with the current view, cyclic nucleotide-gated cation channels do not need a boost by Cl(-) channels to achieve near-physiological levels of olfaction

Differential cAMP signaling at hippocampal output synapses

cAMP is a critical second messenger involved in synaptic transmission and synaptic plasticity. Here, we show that activation of the adenylyl cyclase by forskolin and application of the cAMP-analog Sp-5,6-DCl-cBIMPS both mimicked and occluded tetanus-induced long-term potentiation (LTP) in subicular bursting neurons, but not in subicular regular firing cells. Furthermore, LTP in bursting cells was inhibited by protein kinase A (PKA) inhibitors Rp-8-CPT-cAMP and H-89. Variations in the degree of EPSC blockade by the low-affinity competitive AMPA receptor-antagonist {gamma}-d-glutamyl-glycine ({gamma}-DGG), analysis of the coefficient of variance as well as changes in short-term potentiation suggest an increase of glutamate concentration in the synaptic cleft after expression of LTP. We conclude that presynaptic LTP in bursting cells requires activation of PKA by a calcium-dependent adenylyl cyclase while LTP in regular firing cells is independent of elevated cAMP levels. Our results provide evidence for a differential role of cAMP in LTP at hippocampal output synapses

Cellular and synaptic diversity of layer 2-3 pyramidal neurons in human individuals

Understanding the functional principles of the human brain requires deep insight into the neuronal and network physiology. To what extent such principles of cellular physiology and synaptic interactions are common across different human individuals is unknown. We characterized the physiology of ~1200 pyramidal neurons and ~1400 monosynaptic connections using advanced multineuron patch-clamp recordings in slices from human temporal cortex. To disentangle within and between individual sources of heterogeneity, we recorded up to 100 neurons per single subject. We found that neuronal, but not synaptic physiology varied with laminar depth. Connection probability was ~15% throughout layer 2-3. Synaptic amplitudes exhibited heavy-tailed distributions with an inverse power law relationship to short term plasticity. Neurons could be classified into four functional subtypes. These general principles of microcircuit physiology were common across individuals. Our study advances the understanding of human neuron and synaptic diversity from an individual and phenotypic perspective

Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopaty

The stratum lacunosum moleculare (SLM) is the connection hub between entorhinal cortex and hippocampus, two brain regions that are most vulnerable in Alzheimer’s disease. We recently identified a specific synaptic deficit of Nectin-3 in transgenic models for tauopathy. Here we defined cognitive impairment and electrophysiological problems in the SLM of Tau.P301L mice, which corroborated the structural defects in synapses and dendritic spines. Reduced diffusion of DiI from the ERC to the hippocampus indicated defective myelinated axonal pathways. Ultrastructurally, myelinated axons in the temporoammonic pathway (TA) that connects ERC to CA1 were damaged in Tau.P301L mice at young age. Unexpectedly, the myelin defects were even more severe in bigenic biGT mice that co-express GSK3β with Tau.P301L in neurons. Combined, our data demonstrate that neuronal expression of protein Tau profoundly affected the functional and structural organization of the entorhinal-hippocampal complex, in particular synapses and myelinated axons in the SLM. White matter pathology deserves further attention in patients suffering from tauopathy and Alzheimer’s disease

Muscarinic acetylcholine receptors and voltage-gated calcium channels contribute to bidirectional synaptic plasticity at CA1-subiculum synapses

Hippocampal output is mediated via the subiculum, which is the principal target of CA1 pyramidal cells, and which sends projections to a variety of cortical and subcortical regions. Pyramidal cells in the subiculum display two different firing modes and are classified as being burst-spiking or regular-spiking. In a previous study, we found that low-frequency stimulation induces an NMDA receptor-dependent long-term depression (LTD) in burst-spiking cells and a metabotropic glutamate receptor-dependent long-term potentiation (LTP) in regular-spiking cells [P. Fidzinski, O. Shor, J. Behr, Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses, Eur. J. Neurosci., 27 (2008) 1111-1118]. Here, we present evidence that this bidirectional plasticity relies upon the co-activation of muscarinic acetylcholine receptors, as scopolamine blocks synaptic plasticity in both cell types. In addition, we demonstrate that the L-type calcium channel inhibitor nifedipine converts LTD to LTP in burst-spiking cells and LTP to LTD in regular-spiking cells, indicating that the polarity of synaptic plasticity is modulated by voltage-gated calcium channels. Bidirectional synaptic plasticity in subicular cells therefore appears to be governed by a complex signaling system, involving cell-specific recruitment of ligand and voltage-gated ion channels as well as metabotropic receptors. This complex regulation might be necessary for fine-tuning of synaptic efficacy at hippocampal output synapses

Synaptic plasticity in the subiculum

The subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal-cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1-subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1-subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output

Reduced threshold for induction of LTP by activation of dopamine D1/D5 receptors at hippocampal CA1–subiculum synapses

The phasic release of dopamine in the hippocampal formation has been shown to facilitate the encoding of novel information. There is evidence that the subiculum operates as a detector and distributor of sensory information, which incorporates the novelty and relevance of signals received from CA1. The subiculum acts as the final hippocampal relay station for outgoing information. Subicular pyramidal cells have been classified as regular- and burst-spiking neurons. The goal of the present study was to study the effect of dopamine D1/D5 receptor activation on synaptic transmission and plasticity in the subicular regular-spiking neurons of 4–6 week old Wistar rats. We demonstrate that prior activation of D1/D5 receptors reduces the threshold for the induction of long-term potentiation (LTP) in subicular regular-spiking neurons. Our results indicate that D1/D5 receptor activation facilitates a postsynaptic form of LTP in subicular regular-spiking cells that is NMDA receptor-dependent, relies on postsynaptic Ca2+ signaling, and requires the activation of protein kinase A. The enhanced propensity of subicular regular-spiking cells to express postsynaptic LTP after activation of D1/D5 receptors provides an intriguing mechanism for the encoding of hippocampal output information

M-current-mediated neuronal modulation

Boehlen A, Schwake M, Dost R, et al. The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology. 2013;168(5):1182-1200.Background and Purpose: KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential. Experimental Approach: The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro. Key Results: 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of γ and θ oscillation peak power, with no significant change in oscillation frequency. Conclusion and Implications: Our data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo