Marlene Bartos

Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.

Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks

Networks of GABAergic interneurons are of critical importance for the generation of gamma frequency oscillations in the brain. To examine the underlying synaptic mechanisms, we made paired recordings from “basket cells” (BCs) in different subfields of hippocampal slices, using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the parvalbumin promoter. Unitary inhibitory postsynaptic currents (IPSCs) showed large amplitude and fast time course with mean amplitude-weighted decay time constants of 2.5, 1.2, and 1.8 ms in the dentate gyrus, and the cornu ammonis area 3 (CA3) and 1 (CA1), respectively (33–34°C). The decay of unitary IPSCs at BC–BC synapses was significantly faster than that at BC–principal cell synapses, indicating target cell-specific differences in IPSC kinetics. In addition, electrical coupling was found in a subset of BC–BC pairs. To examine whether an interneuron network with fast inhibitory synapses can act as a gamma frequency oscillator, we developed an interneuron network model based on experimentally determined properties. In comparison to previous interneuron network models, our model was able to generate oscillatory activity with higher coherence over a broad range of frequencies (20–110 Hz). In this model, high coherence and flexibility in frequency control emerge from the combination of synaptic properties, network structure, and electrical coupling.

Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates.

Networks of GABAergic neurons are key elements in the generation of gamma oscillations in the brain. Computational studies suggested that the emergence of coherent oscillations requires hyperpolarizing inhibition. Here, we show that GABA(A) receptor-mediated inhibition in mature interneurons of the hippocampal dentate gyrus is shunting rather than hyperpolarizing. Unexpectedly, when shunting inhibition is incorporated into a structured interneuron network model with fast and strong synapses, coherent oscillations emerge. In comparison to hyperpolarizing inhibition, networks with shunting inhibition show several advantages. First, oscillations are generated with smaller tonic excitatory drive. Second, network frequencies are tuned to the gamma band. Finally, robustness against heterogeneity in the excitatory drive is markedly improved. In single interneurons, shunting inhibition shortens the interspike interval for low levels of drive but prolongs it for high levels, leading to homogenization of neuronal firing rates. Thus, shunting inhibition may confer increased robustness to gamma oscillations in the brain.

Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons

Hippocampal theta (5–10 Hz) and gamma (35–85 Hz) oscillations depend on an inhibitory network of GABAergic interneurons. However, the lack of methods for direct and cell-type-specific interference with inhibition has prevented better insights that help link synaptic and cellular properties with network function. Here, we generated genetically modified mice (PV-Δγ2) in which synaptic inhibition was ablated in parvalbumin-positive (PV+) interneurons. Hippocampal local field potential and unit recordings in the CA1 area of freely behaving mice revealed that theta rhythm was strongly reduced in these mice. The characteristic coupling of theta and gamma oscillations was strongly altered in PV-Δγ2 mice more than could be accounted for by the reduction in theta rhythm only. Surprisingly, gamma oscillations were not altered. These data indicate that synaptic inhibition onto PV+ interneurons is indispensable for theta- and its coupling to gamma oscillations but not for rhythmic gamma-activity in the hippocampus. Similar alterations in rhythmic activity were obtained in a computational hippocampal network model mimicking the genetic modification, suggesting that intrahippocampal networks might contribute to these effects.

Postnatal differentiation of basket cells from slow to fast signaling devices

Gamma frequency (30–100 Hz) oscillations in the mature cortex underlie higher cognitive functions. Fast signaling in GABAergic interneuron networks plays a key role in the generation of these oscillations. During development of the rodent brain, gamma activity appears at the end of the first postnatal week, but frequency and synchrony reach adult levels only by the fourth week. However, the mechanisms underlying the maturation of gamma activity are unclear. Here we demonstrate that hippocampal basket cells (BCs), the proposed cellular substrate of gamma oscillations, undergo marked changes in their morphological, intrinsic, and synaptic properties between postnatal day 6 (P6) and P25. During maturation, action potential duration, propagation time, duration of the release period, and decay time constant of IPSCs decreases by ∼30–60%. Thus, postnatal development converts BCs from slow into fast signaling devices. Computational analysis reveals that BC networks with young intrinsic and synaptic properties as well as reduced connectivity generate oscillations with moderate coherence in the lower gamma frequency range. In contrast, BC networks with mature properties and increased connectivity generate highly coherent activity in the upper gamma frequency band. Thus, late postnatal maturation of BCs enhances coherence in neuronal networks and will thereby contribute to the development of cognitive brain functions.

Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory

Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons

Fast-spiking, parvalbumin-expressing basket cells (BCs) play a key role in feedforward and feedback inhibition in the hippocampus. However, the dendritic mechanisms underlying rapid interneuron recruitment have remained unclear. To quantitatively address this question, we developed detailed passive cable models of BCs in the dentate gyrus based on dual somatic or somatodendritic recordings and complete morphologic reconstructions. Both specific membrane capacitance and axial resistivity were comparable to those of pyramidal neurons, but the average somatodendritic specific membrane resistance (Rm) was substantially lower in BCs. Furthermore, Rm was markedly nonuniform, being lowest in soma and proximal dendrites, intermediate in distal dendrites, and highest in the axon. Thus, the somatodendritic gradient of Rm was the reverse of that in pyramidal neurons. Further computational analysis revealed that these unique cable properties accelerate the time course of synaptic potentials at the soma in response to fast inputs, while boosting the efficacy of slow distal inputs. These properties will facilitate both rapid phasic and efficient tonic activation of BCs in hippocampal microcircuits.

Functional characteristics of parvalbumin- and cholecystokinin-expressing basket cells

Abstract  Cortical neuronal network operations depend critically on the recruitment of GABAergic interneurons and the properties of their inhibitory output signals. Recent evidence indicates a marked difference in the signalling properties of two major types of perisomatic inhibitory interneurons, the parvalbumin‐ and the cholecystokinin‐containing basket cells. Parvalbumin‐expressing basket cells are rapidly recruited by excitatory synaptic inputs, generate high‐frequency trains of action potentials, discharge single action potentials phase‐locked to fast network oscillations and provide fast, stable and timed inhibitory output onto their target cells. In contrast, cholecystokinin‐containing basket cells are recruited in a less reliable manner, discharge at moderate frequencies with single action potentials weakly coupled to the phases of fast network oscillations and generate an asynchronous, fluctuating and less timed inhibitory output. These signalling modes are based on cell type‐dependent differences in the functional and plastic properties of excitatory input synapses, integrative qualities and in the kinetics and dynamics of inhibitory output synapses. Thus, the two perisomatic inhibitory interneuron types operate with different speed and precision and may therefore contribute differently to the operations of neuronal networks.

Associative Plasticity at Excitatory Synapses Facilitates Recruitment of Fast-Spiking Interneurons in the Dentate Gyrus

Fast-spiking perisomatic-inhibitory interneurons (PIIs) receive convergent excitation and mediate both feedforward and feedback inhibition in cortical microcircuits. However, it remains poorly understood how convergent excitatory inputs recruit PIIs to produce precisely timed inhibition. Here, we analyzed the interaction of inputs from the entorhinal cortex [perforant path (PP)] and from local granule cells [mossy fibers (MFs)] onto PIIs in the rat dentate gyrus (DG). PP stimulation alone activates PIIs with low temporal precision. Interestingly, when PP and MFs are coactivated with a 10 ms delay, PIIs discharge with precise timing. Moreover, repeated coactivation of the two inputs induces associative long-term potentiation (LTP) at MF synapses. Under these conditions, a single potentiated MF input is sufficient to recruit PIIs in a reliable and highly precise manner to provide feedback inhibition. MF-LTP depends on the discharge of PIIs, indicating Hebbian plasticity. However, MF-LTP is preserved when NMDA receptors are blocked but depends on transmission through Ca2+-permeable AMPA receptors (AMPARs). PP–PII synapses, in contrast, lack Ca2+-permeable AMPARs and do not show plasticity on associative activation. Thus, precise recruitment of PIIs requires excitation through MF–PII synapses during feedforward activation. We propose that associative plasticity at these synapses is a central mechanism that adjusts inhibition levels to maintain sparse activity and to improve signal-to-noise ratio in the DG network.

Morpho‐physiological criteria divide dentate gyrus interneurons into classes

GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock‐in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)‐positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross‐correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity.