Anja Gundlfinger

Adenosine modulates transmission at the hippocampal mossy fibre synapse via direct inhibition of presynaptic calcium channels

The modulation of synaptic transmission by presynaptic ionotropic and metabotropic receptors is an important means to control and dynamically adjust synaptic strength. Even though synaptic transmission and plasticity at the hippocampal mossy fibre synapse are tightly controlled by presynaptic receptors, little is known about the downstream signalling mechanisms and targets of the different receptor systems. In the present study, we identified the cellular signalling cascade by which adenosine modulates mossy fibre synaptic transmission. By means of electrophysiological and optical recording techniques, we found that adenosine activates presynaptic A1 receptors and reduces Ca2+ influx into mossy fibre terminals. Ca2+ currents are directly modulated via a membrane‐delimited pathway and the reduction of presynaptic Ca2+ influx can explain the inhibition of synaptic transmission. Specifically, we found that adenosine modulates both P/Q‐ and N‐type presynaptic voltage‐dependent Ca2+ channels and thereby controls transmitter release at the mossy fibre synapse.

Inhibitory Gradient along the Dorsoventral Axis in the Medial Entorhinal Cortex

Local inhibitory microcircuits in the medial entorhinal cortex (MEC) and their role in network activity are little investigated. Using a combination of electrophysiological, optical, and morphological circuit analysis tools, we find that layer II stellate cells are embedded in a dense local inhibitory microcircuit. Specifically, we report a gradient of inhibitory inputs along the dorsoventral axis of the MEC, with the majority of this local inhibition arising from parvalbumin positive (PV+) interneurons. Finally, the gradient of PV+ fibers is accompanied by a gradient in the power of extracellular network oscillations in the gamma range, measured both in vitro and in vivo. The reported differences in the inhibitory microcircuitry in layer II of the MEC may therefore have a profound functional impact on the computational working principles at different locations of the entorhinal network and influence the input pathways to the hippocampus.

Phase precession through synaptic facilitation

Phase precession is a relational code that is thought to be important for episodic-like memory, for instance, the learning of a sequence of places. In the hippocampus, places are encoded through bursting activity of so-called place cells. The spikes in such a burst exhibit a precession of their firing phases relative to field potential theta oscillations (412 Hz); the theta phase of action potentials in successive theta cycles progressively decreases toward earlier phases. The mechanisms underlying the generation of phase precession are, however, unknown. In this letter, we show through mathematical analysis and numerical simulations that synaptic facilitation in combination with membrane potential oscillations of a neuron gives rise to phase precession. This biologically plausible model reproduces experimentally observed features of phase precession, such as (1) the progressive decrease of spike phases, (2) the nonlinear and often also bimodal relation between spike phases and the animals place, (3) the range of phase precession being smaller than one theta cycle, and (4) the dependence of phase jitter on the animals location within the place field. The model suggests that the peculiar features of the hippocampal mossy fiber synapse, such as its large efficacy, long-lasting and strong facilitation, and its phase-locked activation, are essential for phase precession in the CA3 region of the hippocampus.

Munc13-2 Differentially Affects Hippocampal Synaptic Transmission and Plasticity

The short-term dynamics of synaptic communication between neurons provides neural networks with specific frequency-filter characteristics for information transfer. The direction of short-term synaptic plasticity, that is, facilitation versus depression, is highly dependent on and inversely correlated to the basal release probability of a synapse. Amongst the processes implicated in shaping the release probability, proteins that regulate the docking and priming of synaptic vesicles at the active zone are of special importance. Here, we found that a member of the Munc13 protein family of priming proteins, namely Munc13-2, is essential for normal release probability at hippocampal mossy fiber synapses. Paired pulse and frequency facilitation were strongly increased, whereas mossy fiber long-term potentiation was unaffected in the absence of Munc13-2. In contrast, transmission at 3 other types of hippocampal synapses, Schaffer-collateral, associational-commissural, as well as inhibitory synapses onto CA3 pyramidal neurons was unaffected by the loss of Munc13-2.

Temporal compression mediated by short-term synaptic plasticity

Time scales of cortical neuronal dynamics range from few milliseconds to hundreds of milliseconds. In contrast, behavior occurs on the time scale of seconds or longer. How can behavioral time then be neuronally represented in cortical networks? Here, using electrophysiology and modeling, we offer a hypothesis on how to bridge the gap between behavioral and cellular time scales. The core idea is to use a long time constant of decay of synaptic facilitation to translate slow behaviorally induced temporal correlations into a distribution of synaptic response amplitudes. These amplitudes can then be transferred to a sequence of action potentials in a population of neurons. These sequences provide temporal correlations on a millisecond time scale that are able to induce persistent synaptic changes. As a proof of concept, we provide simulations of a neuron that learns to discriminate temporal patterns on a time scale of seconds by synaptic learning rules with a millisecond memory buffer. We find that the conversion from synaptic amplitudes to millisecond correlations can be strongly facilitated by subthreshold oscillations both in terms of information transmission and success of learning.

Anatomical Organization and Spatiotemporal Firing Patterns of Layer 3 Neurons in the Rat Medial Entorhinal Cortex

Layer 3 of the medial entorhinal cortex is a major gateway from the neocortex to the hippocampus. Here we addressed structure–function relationships in medial entorhinal cortex layer 3 by combining anatomical analysis with juxtacellular identification of single neurons in freely behaving rats. Anatomically, layer 3 appears as a relatively homogeneous cell sheet. Dual-retrograde neuronal tracing experiments indicate a large overlap between layer 3 pyramidal populations, which project to ipsilateral hippocampus, and the contralateral medial entorhinal cortex. These cells were intermingled within layer 3, and had similar morphological and intrinsic electrophysiological properties. Dendritic trees of layer 3 neurons largely avoided the calbindin-positive patches in layer 2. Identification of layer 3 neurons during spatial exploration (n = 17) and extracellular recordings (n = 52) pointed to homogeneous spatial discharge patterns. Layer 3 neurons showed only weak spiking theta rhythmicity and sparse head-direction selectivity. A majority of cells (50 of 69) showed no significant spatial modulation. All of the ∼28% of neurons that carried significant amounts of spatial information (19 of 69) discharged in irregular spatial patterns. Thus, layer 3 spatiotemporal firing properties are remarkably different from those of layer 2, where theta rhythmicity is prominent and spatially modulated cells often discharge in grid or border patterns. SIGNIFICANCE STATEMENT Neurons within the superficial layers of the medial entorhinal cortex (MEC) often discharge in border, head-direction, and theta-modulated grid patterns. It is still largely unknown how defined discharge patterns relate to cellular diversity in the superficial layers of the MEC. In the present study, we addressed this issue by combining anatomical analysis with juxtacellular identification of single layer 3 neurons in freely behaving rats. We provide evidence that the anatomical organization and spatiotemporal firing properties of layer 3 neurons are remarkably different from those in layer 2. Specifically, most layer 3 neurons discharged in spatially irregular firing patterns, with weak theta-modulation and head-directional selectivity. This work thus poses constraints on the spatiotemporal patterns reaching downstream targets, like the hippocampus.

Differential modulation of short‐term synaptic dynamics by long‐term potentiation at mouse hippocampal mossy fibre synapses

Synapses continuously experience short‐ and long‐lasting activity‐dependent changes in synaptic strength. Long‐term plasticity refers to persistent alterations in synaptic efficacy, whereas short‐term plasticity (STP) reflects the instantaneous and reversible modulation of synaptic strength in response to varying presynaptic stimuli. The hippocampal mossy fibre synapse onto CA3 pyramidal cells is known to exhibit both a presynaptic, NMDA receptor‐independent form of long‐term potentiation (LTP) and a pronounced form of STP. A detailed description of their exact interdependence is, however, lacking. Here, using electrophysiological and computational techniques, we have developed a descriptive model of transmission dynamics to quantify plasticity at the mossy fibre synapse. STP at this synapse is best described by two facilitatory processes acting on time‐scales of a few hundred milliseconds and about 10 s. We find that these distinct types of facilitation are differentially influenced by LTP such that the impact of the fast process is weakened as compared to that of the slow process. This attenuation is reflected by a selective decrease of not only the amplitude but also the time constant of the fast facilitation. We henceforth argue that LTP, involving a modulation of parameters determining both amplitude and time course of STP, serves as a mechanism to adapt the mossy fibre synapse to its temporal input.

Natural Spike Trains Trigger Short- and Long-Lasting Dynamics at Hippocampal Mossy Fiber Synapses in Rodents

Background Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular. Methodology/Principal Findings Using extracellular and whole-cell electrophysiological recordings, we have here studied the synaptic responses at hippocampal mossy fiber synapses in vitro to stimulus patterns obtained from in vivo recordings of place cell firing of dentate gyrus granule cells in behaving rodents. We find that synaptic strength is strongly modulated on short- and long-lasting time scales during the presentation of the natural stimulus trains. Conclusions/Significance We conclude that dynamic short- and long-term synaptic plasticity at the hippocampal mossy fiber synapse plays a prominent role in normal synaptic function.

Circuit Mechanisms of Memory Formation

Memory formation is one of the most fascinating and complex brain functions. A large body of research over the last decades has drastically increased our understanding of the molecular and cellular processes underlying learning, most notably through a detailed investigation of synaptic plasticity. This reductionist approach, typically involving in vitro experiments, has been tremendously successful in providing a mechanistic framework for learning at the level of single neurons. However, real-life memories are formed through dynamic interactions of many neurons embedded in large networks. Investigating the mechanisms and consequences of learning at the level of neuronal circuits is technically much more demanding, and we are only beginning to understand this important topic. This special issue presents recent progress in illuminating the most exciting issues in the field of circuit mechanisms of memory formation. The contributing articles cover essential concepts and hypotheses underlying memory formation ranging from synaptic mechanisms of plasticity in neuronal microcircuits to circuit reorganizations in response to physiological and pathological influences.

Retrograde Signaling Causes Excitement

Retrograde signaling is a powerful tool to shape synaptic transmission, typically inducing inhibition of transmitter release. A new study published in this issue of Neuron by Carta et al. (2014) now provides strong support for arachidonic acid as a potentiating retrograde messenger.