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Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumeriliiciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

Serotonin (5-HT) is crucial for regulating brain functions such as mood, sleep, and cognition. This study presents a comprehensive transcriptomic analysis of 5-HT receptors (Htrs) across ≈4 million cells in the adult mouse brain using single-cell RNA sequencing (scRNA-seq) data from the Allen Institute. We observed differential transcription patterns of all 14 Htr subtypes, revealing diverse prevalence and distribution across cell classes. Remarkably, we found that 65.84% of cells transcribe RNA of at least one Htr, with frequent co-transcription of multiple Htrs, underscoring the complexity of the 5-HT system even at the single-cell dimension. Leveraging a multiplexed error-robust fluorescence in situhybridization (MERFISH) dataset provided by Harvard University of ≈10 million cells, we analyzed the spatial distribution of each Htr, confirming previous findings and uncovering novel transcription patterns. To aid in exploring Htr transcription, we provide an online interactive visualizer.

Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving organisms. Although their application in neuroscience has traditionally focused on the control of spiking activity at the somatodendritic level, the scope of optogenetic modulators for direct manipulation of presynaptic functions is growing. Presynaptically localized opsins combined with light stimulation at the terminals allow light-mediated neurotransmitter release, presynaptic inhibition, induction of synaptic plasticity and specific manipulation of individual components of the presynaptic machinery. Here, we describe presynaptic applications of optogenetic tools in the context of the unique cell biology of axonal terminals, discuss their potential shortcomings and outline future directions for this rapidly developing research area.

Cell assemblies and central pattern generators (CPGs) are related types of neuronal networks: both consist of interacting groups of neurons whose collective activities lead to defined functional outputs. In the case of a cell assembly, the functional output may be interpreted as a representation of something in the world, external or internal; for a CPG, the output ‘drives’ an observable (i.e. motor) behavior. Electrical coupling, via gap junctions, is critical for the development of CPGs, as well as for their actual operation in the adult animal. Electrical coupling is also known to be important in the development of hippocampal and neocortical principal cell networks. We here argue that electrical coupling – in addition to chemical synapses – may therefore contribute to the formation of at least some cell assemblies in adult animals.

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders.

Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from neuronal synchronization to the regulation of synaptic plasticity, which are specific to the particular mechanism of spikelet generation. As spikelets reflect spiking activity in neuronal compartments that are electrotonically distinct from the soma, four modes of spikelet generation can be envisaged: (1) dendritic spikes or (2) axonal action potentials occurring in a single cell as well as action potentials transmitted via (3) gap junctions or (4) ephaptic coupling in pairs of neurons. In one of the best studied neuron type, cortical pyramidal neurons, the origins and functions of spikelets are still unresolved; all four potential mechanisms have been proposed, but the experimental evidence remains ambiguous. Here we attempt to reconcile the scattered experimental findings in a coherent theoretical framework. We review in detail the various mechanisms that can give rise to spikelets. For each mechanism, we present the biophysical underpinnings as well as the resulting properties of spikelets and compare these predictions to experimental data from pyramidal neurons. We also discuss the functional implications of each mechanism. On the example of pyramidal neurons, we illustrate that several independent spikelet-generating mechanisms fulfilling vastly different functions might be operating in a single cell.

Nutritional intervention with the natural polyamine spermidine, an autophagy-enhancing agent, can prevent memory loss in aging model organisms. This is the first human study to evaluate the impact of spermidine supplementation on memory performance in older adults at risk for the development of Alzheimer's disease.

The role of mossy cells (MCs) of the hippocampal dentate area has long remained mysterious. Recent research has begun to unveil their significance in spatial computation of the hippocampus. Here, we used an in vitromodel of sharp wave-ripple complexes (SWRs), which contribute to hippocampal memory formation, to investigate MC involvement in this fundamental population activity. We find that a significant fraction of MCs (∼47%) is recruited into the active neuronal network during SWRs in the CA3 area. Moreover, MCs receive pronounced, ripple-coherent, excitatory and inhibitory synaptic input. Finally, we find evidence for SWR-related synaptic activity in granule cells that is mediated by MCs. Given the widespread connectivity of MCs within and between hippocampi, our data suggest a role for MCs as a hub functionally coupling the CA3 and the DG during ripple-associated computations.

The distinctive firing pattern of grid cells in the medial entorhinal cortex (MEC) supports its role in the representation of space. It is widely believed that the hexagonal firing field of grid cells emerges from neural dynamics that depend on the local microcircuitry. However, local networks within the MEC are still not sufficiently characterized. Here, applying up to eight simultaneous whole-cell recordings in acute brain slices, we demonstrate the existence of unitary excitatory connections between principal neurons in the superficial layers of the MEC. In particular, we find prevalent feed-forward excitation from pyramidal neurons in layer III and layer II onto stellate cells in layer II, which might contribute to the generation or the inheritance of grid cell patterns.

Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes.

Viele neuronale Netzwerke zeigen kohärente rhythmische Aktivität. Diese Netzwerkoszillationen bilden eine zeitliche Referenz für die Aktivität einzelner Neurone und erlauben so die Entstehung raum-zeitlicher Muster mit definierten Phasenbeziehungen von Aktionspotenzialen. Häufig kann ein Kerngebiet des Gehirns verschiedene Rhythmen ausbilden, die sich zeitlich überlagern oder alternativ, je nach funktionellem Zustand des Gehirns isoliert auftreten. In den letzten 20 Jahren wurde der Hippocampus des Säugers zu einem wichtigen Modellsystem für das Studium von Netzwerkoszillationen. Hier wurden grundlegende zelluläre Mechanismen der neuronalen Koordination erarbeitet, zugleich aber auch Modelle entwickelt, wie diese koordinierten Muster zur Entstehung, Konsolidierung und zum Abruf von Gedächtnisinhalten führen. Für die Neurowissenschaften stellen solche räumlich-zeitlichen Aktivitätsmuster in neuronalen Netzwerken eine wichtige Ebene der Analyse dar, die zwischen zellulären Mechanismen und systemischen Funktionen vermittelt. Am Beispiel eines besonders schnellen Oszillationsmusters, der hippocampalen ‚ripples‘, sollen der aktuelle Kenntnisstand der Forschung, aber auch die Fülle der noch offenen Fragen dargestellt werden.

The decrease in brain CO2partial pressure (pCO2) that takes place both during voluntary and during pathological hyperventilation is known to induce gross alterations in cortical functions that lead to subjective sensations and altered states of consciousness. The mechanisms that mediate the effects of the decrease in pCO2at the neuronal network level are largely unexplored. In the present work, the modulation of gamma oscillations by hypocapnia was studied in rat hippocampal slices. Field potential oscillations were induced by the cholinergic agonist carbachol under anN-methyl-D-aspartate (NMDA)-receptor blockade and were recorded in the dendritic layer of the CA3 region with parallel measurements of changes in interstitial and intraneuronal pH (pHoand pHi, respectively). Hypocapnia from 5 to 1% CO2led to a stable monophasic increase of 0.5 and 0.2 units in pHoand pHi, respectively. The mean oscillation frequency increased slightly but significantly from 32 to 34 Hz and the mean gamma-band amplitude (20 to 80 Hz) decreased by 20%. Hypocapnia induced a dramatic enhancement of the temporal stability of the oscillations, as was indicated by a two-fold increase in the exponential decay time constant fitted to the autocorrelogram. A rise in pHievoked by the weak base trimethylamine (TriMA) was associated with a slight increase in oscillation frequency (37 to 39 Hz) and a decrease in amplitude (30%). Temporal stability, on the other hand, was decreased by TriMA, which suggests that its enhancement in 1% CO2was related to the rise in pHo. In 1% CO2, the decay-time constant of the evoked monosynaptic pyramidal inhibitory postsynaptic current (IPSC) was unaltered but its amplitude was enhanced. This increase in IPSC amplitude seems to significantly contribute to the enhancement of temporal stability because the enhancement was almost fully reversed by a low concentration of bicuculline. These results suggest that changes in brain pCO2can have a strong influence on the temporal modulation of gamma rhythms.

Hippocampal slices bathed in 4-aminopyridine (4-AP, ≤200 μM) exhibit1) spontaneous large inhibitory postsynaptic potentials (IPSPs) in pyramidal cells, which occur without the necessity of fast glutamatergic receptors, and which hence are presumed to arise from coordinated firing in populations of interneurons; 2) spikes of variable amplitude, presumed to be of antidromic origin, in some pyramidal cells during the large IPSP; 3) bursts of action potentials in selected populations of interneurons, occurring independently of fast glutamatergic and of GABAAreceptors. We have used neuron pairs, and a large network model (3,072 pyramidal cells, 384 interneurons), to examine how these phenomena might be inter-related. Network bursts in electrically coupled interneurons have previously been shown to be possible with dendritic gap junctions, when the dendrites were capable of spike initiation, and when action potentials could cross from cell to cell via gap junctions; recent experimental data showing that dendritic gap junctions between cortical interneurons lead to coupling potentials of only about 0.5 mV argue against this mechanism, however. We now show that axonal gap junctions between interneurons could also lead to network bursts; this concept is consistent with the occurrence of spikelets and partial spikes in at least some interneurons in 4-AP. In our model, spontaneous antidromic action potentials can induce spikelets and action potentials in principal cells during the large IPSP. The probability of observing this type of activity increases significantly when axonal gap junctions also exist between pyramidal cells. Sufficient antidromic activity in the model can lead to epileptiform bursts, independent of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) andN-methyl-d-aspartate (NMDA) receptors, in some principal cells, preceded by IPSPs and spikelets. The model predicts that gap junction blockers should suppress large IPSPs observed in 4-AP and should also reduce the probability of observing antidromic activity, or bursting, in pyramidal cells. Experiments show that, indeed, the gap junction blocking compound carbenoxolone does suppress spontaneous large IPSCs, occurring in 4-AP plus ionotropic glutamate blockers, together with a GABABreceptor blocker; carbenoxolone also suppresses large, fast inward currents, corresponding to ectopic spikes, which occur in 4-AP. Carbenoxolone does not suppress large depolarizing IPSPs induced by tetanic stimulation. We conclude that in 4-AP, axonal gap junctions could, at least in principle, account in part for both the large IPSPs, and for the antidromic activity in pyramidal neurons.

Kainate receptors (KARs) are a poorly understood family of ionotropic glutamate receptors. A role for these receptors in the presynaptic control of transmitter release has been proposed but remains controversial. Here, KAR agonists are shown to enhance fiber excitability, and a number of experiments show that this is a direct effect of KARs on the presynaptic fibers. In addition, KAR activation inhibits evoked transmitter release from mossy fiber synapses. Synaptic release of glutamate from either neighboring mossy fiber synapses or associational/commisural (A/C) synapses results in the activation of these presynaptic ionotropic KARs. These results, along with previous studies, indicate that KARs, through the endogenous release of glutamate, mediate excitatory postsynaptic potentials (EPSPs), alter presynaptic excitability, and modulate transmitter release.

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system. The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path–evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined using conventional intracellular and whole cell voltage-clamp recordings. Dopamine (100 μM) depressed alveus-elicited (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated EPSCs to 56 ± 8% of control while perforant path–evoked EPSCs were attenuated to only 76 ± 7% of control. Dopamine had no effect on the EPSC kinetics. Dopamine reduced the frequency of spontaneous miniature EPSCs without affecting their amplitudes. The sensitivity of subicular neurons to the glutamate receptor agonist (S)-α-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid was unchanged by DA pretreatment, excluding a postsynaptic mechanism for the observed reduction of excitatory synaptic transmission. The effect of DA on evoked EPSCs was mimicked by the D1 receptor agonist SFK 38393 and partially antagonized by the D1 receptor antagonist SCH 23390. While the D2 receptor agonist quinelorane failed to reduce the EPSCs, the D2 receptor antagonist sulpiride did not block the action of DA. The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.

Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients’ symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies.

The entorhinal cortex (EC), main input structure to the hippocampus, gets innervated by serotonergic terminals from the raphe nuclei and expresses 5‐HT‐receptors at high density. Using extra‐ and intracellular recording techniques we here investigated the effects of serotonin on population and cellular responses within the EC.Stimulation in the lateral entorhinal cortex resulted in complex field potential responses in the superficial EC. The potentials are composed of an early antidromic and a late orthodromic component reflecting the efferent and afferent circuitry.Serotonin (5‐HT) reduced synaptic potentials of the stimulus evoked extracellular field potential at all concentrations tested (0.1–100 μM; 59%‐depression by 10 μMserotonin), while the antidromic response was not significantly changed by up to 50 μM5‐HT. Depression of field potential responses by serotonin was associated with a significant increase in paired‐pulse facilitation from 1.15 to 1.88.The effects of serotonin on field potential responses were mimicked by 5‐HT1A‐receptor agonists (8‐OH‐DPAT, 5‐CT) and partially prevented by the 5‐HT1A‐receptor antagonist (S‐UH‐301). Moreover, the 5‐HT1A‐receptor antagonist WAY100635 reduced the effect of 5‐CT.Fenfluramine, a serotonin releaser, mimics the effects of serotonin on stimulus‐evoked field potential responses, indicating that synaptically released serotonin can produce the changes in reactivity to afferent stimulation.Depression of isolated AMPA‐receptor mediated EPSCs by serotonin as well as fenfluramine was associated with an increase in paired pulse facilitation, indicating a presynaptic locus of action.We conclude that physiological concentrations of serotonin potently suppresses excitatory synaptic transmission in the superficial entorhinal cortex by a presynaptic mechanism.

1The axonal plexus of most hippocampal interneurons is restricted to certain strata within the target region. This lamination suggests a possible functional heterogeneity of inhibitory synapses between different interneurons and CA1 pyramidal cells.2We therefore compared inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in CA1 pyramidal cells, which were evoked from two stimulation sites (stratum oriens and stratum radiatum). Stimulation in stratum oriens yielded faster decaying IPSPs and IPSCs than stimulation in stratum radiatum.3IPSP and IPSC kinetics were regulated by GABA uptake in both layers as indicated by the prolongation of the signals under tiagabine, a GAT‐1 (neuronal GABA plasma membrane transporter)‐specific GABA‐uptake blocker. However, the effect of tiagabine was significantly more pronounced following stimulation in stratum radiatum than in stratum oriens (prolongation of IPSC half‐decay time by 167 vs.115 %, respectively).4In situhybridization with antisense mRNA for the GABA‐synthesizing enzyme glutamate decarboxylase (GAD65/67) and the GABA transporter GAT‐1 showed that the proportion of interneurons expressing GAT‐1 was lower in stratum oriens than in stratum radiatum/lacunosum‐moleculare.5From these functional and molecular data we conclude that the regulation of IPSP and IPSC kinetics in CA1 pyramidal cells by neuronal GABA uptake differs between layers. Our findings suggest that this laminar difference is caused by a lower expression of GAT‐1 in interneurons in stratum oriens than in stratum radiatum/lacunosum‐moleculare.

1The superficial layers II and III of the entorhinal cortex, which form the main cortical input to the hippocampus, receive a large serotonergic projection from the raphe nuclei and express 5‐HT receptors at high density. Here, we studied the effects of serotonin on the intrinsic properties and excitatory synaptic transmission of the superficial medial entorhinal cortex.2Intracellular and patch clamp recordings revealed that serotonin hyperpolarized only one‐third of the cells, approximately, through a potassium conductance via a GTP‐dependent process.3Serotonin depressed mixed as well as isolated α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐ propionic acid receptor (AMPAR)‐ and N‐methyl‐D‐aspartic acid receptor (NMDAR)‐mediated excitatory postsynaptic potentials/currents (EPSPs/EPSCsapproximately 40 % reduction with 1 μM serotonin).4The effect of serotonin on EPSPs/EPSCs was similar in whole‐cell versusintracellular recordings; it did not require intracellular GTP and was not visible in glutamate applications to excised patches. Miniature EPSCs recorded in the presence of tetrodotoxin and bicuculline were reduced in frequency, but not altered in amplitude.5The effects of serotonin on intrinsic properties and EPSPs were partially mimicked by 5‐HT1Areceptor agonists (±)‐8‐hydroxy‐2‐(di‐n‐propylamino)tetralin hydrobromide (8‐OH‐DPAT) and 5‐carboxamido‐tryptamine maleate (5‐CT), and reduced by 5‐HT1Areceptor antagonists S‐(‐)‐5‐fluoro‐8‐hydroxy‐DPAT hydrochloride (S‐UH‐301), 1‐(2‐methoxyphenyl)‐4‐[4‐(2‐phthalimido)butyl]piperazine hydrobromide (NAN‐190) and spiperone.6We conclude that serotonin potently suppresses excitatory synaptic transmission via 5‐HT1Areceptors in layers II and III of the medial entorhinal cortex by a presynaptic mechanism.

Schmitz, Dietmar, Tengis Gloveli, Ruth M. Empson, and Uwe Heinemann.Serotonin reduces polysynaptic inhibition via 5-HT1Areceptors in the superficial entorhinal cortex. J. Neurophysiol.80: 1116–1121, 1998. The superficial cells of the entorhinal cortex (EC), main input to the hippocampus, receive a serotonergic input from the raphe nuclei and express 5-hydroxytryptamine creatine sulfate complex (5-HT) receptors at high density. With the use of intracellular recordings, we investigated the effects of serotonin on synaptic inhibition of layer II and III neurons of the EC. Serotonin reduced both polysynaptic fast and slow inhibitory postsynaptic potentials (IPSPs) in projection neurons of the superficial EC. Polysynaptic fast and slow IPSPs were depressed by serotonin in a dose-dependent manner (0.1–100 μM). Serotonin in a concentration of 1 μM reduced the amplitudes of polysynaptic fast and slow IPSPs by ∼40 and 50%, respectively. To identify the subtype of the 5-HT–receptor mediating the effects on polysynaptic IPSPs, we applied various 5-HT–receptor agonists and antagonists. Although the serotonin agonists for the 5-HT1B,2C,3receptors were ineffective, the effects were mimicked by the 5-HT1A–receptor agonists (8-OH-DPAT, 5-CT) and prevented by the 5-HT1A–receptor antagonist NAN-190. To look at the direct effects of 5-HT on inhibitory interneurons, we elicited monosynaptic IPSPs in the absence of excitatory synaptic transmisson. In contrast to the polysynaptic IPSPs, monosynaptic IPSPs were not significantly affected by serotonin. Recordings from putative inhibitory interneurons revealed that their excitatory postsynaptic potentials (EPSPs) were reversibly reduced by serotonin. We conclude that serotonin suppresses polysynaptic inhibition in projection neurons of layers II and III of the EC by depression of EPSPs on inhibitory interneurons via 5-HT1Areceptors.

Gloveli, Tengis, Dietmar Schmitz, Ruth M. Empson, and Uwe Heinemann.Frequency-dependent information flow from the entorhinal cortex to the hippocampus. J. Neurophysiol.78: 3444–3449, 1997. Storage and retrieval of information in the hippocampus is dependent on information transfer from the entorhinal cortex (EC). We studied how the separate pathways from layer II and III of the EC to the hippocampus are selected for information transfer during repetitive synaptic stimulation. Intracellular recordings were made from EC layer II and III projection cells in horizontal combined EC-hippocampal slices. Synaptic responses to stimulation of deep layers or the lateral EC with stimulus intensities ∼70% of that required to elicit an action potential were analyzed during short trains of repetitive stimulation. The threshold intensities for induction of action potentials were in layer II cells 8.2 ± 3.8 (SE) V, significantly larger than 4.4 ± 1.5 V in type 1, and 5.2 ± 3.3 V in type 2 layer III cells, respectively. During repetitive subthreshold stimulation with frequencies below 5 Hz the pathway from the EC layer II remained quiet and was preferentially activated with stimulation frequencies above 5 Hz. In contrast the EC layer III cells responded preferentially to low stimulus frequencies (<10 Hz) and became strongly inhibited when synaptically stimulated with frequencies above 10 Hz. Interestingly during stimulus frequencies between 5 and 10 Hz the likelihood that both layer II and III cells fire was large. Thus a frequency switch operates in the entrohinal cortex regulating output of layer II and III cells to the hippocampus. We suggest that such frequency dependent regulation of information flow presents a new principle of neuronal information processing.

Sharp wave-ripples (SWRs) represent synchronous discharges of hippocampal neurons and are believed to play a major role in memory consolidation. A large body of evidence suggests that SWRs are exclusively generated in the CA3-CA2 network. In contrast, here, we provide several lines of evidence showing that the subiculum can function as a secondary SWRs generator. SWRs with subicular origin propagate forward into the entorhinal cortex as well as backward into the hippocampus proper. Our findings suggest that the output structures of the hippocampus are not only passively facilitating the transfer of SWRs to the cortex, but they also can actively contribute to the genesis of SWRs. We hypothesize that SWRs with a subicular origin may be important for the consolidation of information conveyed to the hippocampus via the temporoammonic pathway.

Up-down states (UDS) are synchronous cortical events of neuronal activity during non-REM sleep. The medial entorhinal cortex (MEC) exhibits robust UDS during natural sleep and under anesthesia. However, little is known about the generation and propagation of UDS-related activity in the MEC. Here, we dissect the circuitry underlying UDS generation and propagation across layers in the MEC using both in vivoand in vitroapproaches. We provide evidence that layer 3 (L3) MEC is crucial in the generation and maintenance of UDS in the MEC. Furthermore, we find that the two sublayers of the L5 MEC participate differentially during UDS. Our findings show that L5b, which receives hippocampal output, is strongly innervated by UDS activity originating in L3 MEC. Our data suggest that L5b acts as a coincidence detector during information transfer between the hippocampus and the cortex and thereby plays an important role in memory encoding and consolidation.

At presynaptic terminals, neurotransmitters are released by synaptic vesicle exocytosis at the active zone. In order to maintain efficient neurotransmission and proper synaptic structure, sites of vesicle fusion must be cleared rapidly by endocytosis. Therefore, the coupling of exo- and endocytosis is crucial. Despite many years of research, the exact molecular and biophysical requirements for the coupling of exo- and endocytosis remain unclear. We investigate whether endocytosis can be triggered in a calcium-independent fashion by evoking calcium-independent exocytosis using a hypertonic sucrose solution. We demonstrate that endocytosis can be triggered, in the absence of calcium influx, in a clathrin-independent manner that relies on actin polymerization. Our findings point to a central role of membrane tension dependent on actin for efficient coupling of exo- and endocytosis.

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