Review

Fast-spiking, parvalbumin+ GABAergic interneurons: From cellular design to microcircuit function

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Science  01 Aug 2014:
Vol. 345, Issue 6196, 1255263
DOI: 10.1126/science.1255263

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  1. Fig. 1 The PV+ interneuron: An interneuron subtype with salient properties and distinct experimental identifiability.

    (A) The placement of PV+ interneurons in interneuron diversity schemes (122). (Left) Scheme showing a subset of the 21 types of GABAergic interneurons currently known in the hippocampal CA1 region. PV+ axo-axonic cells and basket cells are located on the left side. (Right) A PV+ basket cell (probably the most abundant type of PV+ interneuron). Soma and dendrites are shown in orange; axons are depicted in yellow. (B) A PV+ basket cell in the CA1 region of the hippocampus recorded in a freely moving rat. SR, stratum radiatum; SP, stratum pyramidale; SO, stratum oriens. (Upper left inset) Movement trajectory of the animal. (Upper right inset) PV immunoreactivity. (Lower right inset) Electron micrograph of output synapses. Scheme on top is from (87). (C) A basket cell in layer five of the motor cortex (MC). Data are from (123). Color code in (B) and (C): Soma and dendrites are shown in black; axon is depicted in red. (D) Fast-spiking action potential phenotype of a putative PV+ interneuron in the neocortex in vitro. A long somatic current pulse evoked a high-frequency train of action potentials in the intracellularly recorded neuron. Data are from (124). (E) Genetic fluorescent protein labeling of PV+ interneurons, using mice expressing Cre recombinase under the control of the PV promoter. (Left) mCherry labeling after adenoassociated virus infection; (center) PV immunoreactivity; (right), overlay. Inset on top shows targeted PV gene. Scheme on top is (125). (F) Functional labeling of PV+ interneurons, using mice expressing Cre recombinase and channelrhodopsin or halorhodopsin under the control of the PV promoter in vivo. (Left) Identification of unit activity in PV+ interneurons expressing channelrhodopsin in an awake, freely moving mouse recorded with “optrodes.” Data are from (126). (Right) Activity of a PV+ interneuron expressing halorhodopsin in an awake mouse moving on a linear track. Note that the light pulse abolishes action potential (AP) initiation in the PV+ interneuron (top) but increases the action potential frequency in a simultaneously recorded pyramidal neuron (bottom). Data are from (92). CA1, cornu ammonis region 1; CA3, cornu ammonis region 3; PFC, prefrontal cortex.

  2. Fig. 2 The “in” and “out” of PV+ interneurons: dendrites.

    (A) Direct patch-clamp recording from subcellular processes of PV+ interneurons in the dentate gyrus (DG), using confocally targeted patch-clamp recording in a brain slice in vitro. The cell was first loaded with fluorescent dye (Alexa Fluor 488) via a somatic recording pipette. A dendritic recording was subsequently obtained on the distal dendrite. (B) Decremental action potential backpropagation into dendrites. Peak amplitude of the action potential at the dendrite was plotted against distance, with recording sites at basal dendrites (negative distance) and apical dendrites (positive distance). Solid circles, somatic current injection; open circles, dendritic current injection. Inset on top shows action potentials at the soma (black) and dendrite (red), with the current pulse applied to the soma. (C) Dendritic Ca2+ transients in PV+ interneurons in the hippocampal CA1 region in vitro. (Top) Dendritic Ca2+ transients at 10 and 50 μm distance from the soma. (Bottom) Decline of amplitude of dendritic Ca2+ transients as a function of distance from the soma. Error bars indicate SEM. R, red; G, green fluorescent signal. Data are from (30). (D) Dendritic Kv3-type K+ channels in a PV+ interneuron model are locally activated by synaptic input (apical dendrite, arrow). Pseudocolor code indicates the activated K+ conductance (GK). (E) Dendritic Kv3-type K+ channels in PV+ interneurons accelerate the EPSP time course (top) and enhance the ability of the neuron to detect temporally coincident, but spatially distributed inputs (bottom). Blue, passive dendrites; black, K+ channels in synapse-containing dendrites. Gsyn, synaptic peak conductance. Data in (A), (B), (D), and (E) are from (27). (F) Schematic illustration of the different rules of dendritic integration in PV+ interneurons (left) and pyramidal neurons (right). In PV+ interneurons, the high ratio of K+ channels to Na+ channels in dendrites confers linear or sublinear integration (Σ, linear summation mechanism). In pyramidal neurons, the high ratio of Na+ channels to K+ channels in dendrites enriches the repertoire of single-neuron computations [∫, sigmoidal threshold mechanism (127)].

  3. Fig. 3 The “in” and “out” of PV+ interneurons: axons and presynaptic terminals.

    (A) Proximal initiation of action potentials. (Top) Action potentials at the soma (black) and axon (blue) in two different soma-axon recordings with different axonal distance. (Bottom) Latency between action potentials in axon and soma was plotted against distance, with negative values indicating “axon-first” behavior and positive values representing “soma-first” behavior. Note the sharp initiation site in the axon ~20 μm from the soma. (B) Voltage-gated Na+ channel spatial distribution profile. Channel density measured in the outside-out patch configuration is plotted against distance, with negative values indicating dendritic location and positive values indicating axonal location. Note the stepwise increase of Na+ channel density from the soma to the proximal axon, followed by a gradual increase to the distal axon. Data in (A) and (B) are from (43). (C) Tight coupling between Ca2+ channels and release sensors at the output synapses of PV+ interneurons. (Top left) Chemical structure of the fast Ca2+ chelator BAPTA and the slow Ca2+ chelator EGTA used to probe the coupling configuration. (Top right) Concentration dependence of the effects of the two chelators on GABA release. Curves represent linearized models fit to the experimental data, revealing a coupling distance of 12 nm. IPSC, inhibitory postsynaptic current; r, coupling distance; d, mean coupling distance; σ, SD. (Bottom left) Dependence of simulated time course of release on coupling distance in a source-sensor model. (Bottom right) Simulated synaptic delay and half-duration of the time course of release as a function of coupling distance. Data are from (61). (D) Action of the endogenous Ca2+ binding protein PV on transmitter release. (Top left) Secondary structure of PV, with the spheres indicating bound Ca2+ ions. Data are from (128). (Top right) Activity-dependent regulation of PV concentration in interneurons of the hippocampal CA3 region. EE, enriched environment; cFC, contextual fear conditioning. Data are from (69). (Bottom) Estimation of absolute PV concentration in the soma of different types of inhibitory interneurons by calibrated immunocytochemistry. Data are from (10).

  4. Fig. 4 The role of PV+ interneurons in feedforward inhibitory microcircuits.

    (A) Schematic illustration of the feedforward inhibitory microcircuit. IN, interneuron; PN, principal neuron. [Scheme courtesy of G. Buzsáki.] (B) Time course of disynaptic feedforward inhibition in the hippocampal CA1 region. Traces indicate control signal (monosynaptic EPSC and disynaptic IPSC), pharmacologically isolated EPSC, and analog subtraction. Note the short latency of the disynaptic IPSCs (inset). The asterisk indicates delay. Data are from (72). (C) Activation of pyramidal neurons (top), fast-spiking interneurons (center), and regularly spiking interneurons (bottom) during feedforward inhibition. Upper traces show local field potentials; lower traces illustrate loose-patch recordings. Right panels show corresponding morphological properties of the recorded cells. Inset on top schematically illustrates stimulation procedure. Data are from (74). (D) Feedforward inhibition shortens the coincidence detection window in CA1 pyramidal neurons. (Left) Traces indicate action potentials recorded in the cell-attached configuration after stimulation of two Schaffer collateral inputs at different time intervals under control conditions (top) and after a block of inhibition (bottom). Arrows indicate time points of first and second stimulus. (Right) Spike probability after stimulation of two excitatory inputs with time interval Δt in the presence of inhibition (gray bars) and after a block of inhibition (white bars). Error bars denote SEM. Data are from (72). (E) Feedforward inhibition expands the dynamic range of principal neuron population activity. (Left) Plot of proportion of recruited CA1 pyramidal cells (PCs) against synaptic input strength. Filled data points and the black curve show the results for the entire population of CA1 pyramidal neurons; gray curves show the results for individual cells. (Right) Comparison of population input-output curves in the presence of inhibition (solid circles) and after a block of inhibition (open circles). Although PV+ interneurons are likely to play an important role, other interneuron types may also be involved. Data are from (74).

  5. Fig. 5 The role of PV+ interneurons in feedback inhibitory microcircuits.

    (A) Schematic illustration of the feedback inhibitory microcircuit. (Top) Recurrent inhibition; (bottom) lateral inhibition. [Scheme courtesy of G. Buzsáki.] (B) Feedback inhibition in the dentate gyrus. Reciprocal coupling between a fast-spiking (putative PV+) interneuron and a granule cell. Neurons were filled with biocytin during recording and subsequently reconstructed. Black, soma and dendrites of PV+ interneuron; blue, axon of PV+ interneuron; green, soma and dendrites of granule cell; red, granule cell axon. Red dots, putative excitatory synapses on interneurons; green dots, inhibitory synapses on granule cells. H, hilus; GCL, granule cell layer. Data are from (23). (C) Feedback inhibition in the entorhinal cortex (EC). Simultaneous recording from one fast-spiking (putative PV+) interneuron and three layer-two stellate cells. (Left) Action potential phenotype of the four neurons. (Center) Action potentials in a stellate cell evoked EPSPs in the putative PV+ interneuron. (Right) Action potentials in the interneuron evoked IPSPs in all three stellate cells. (Top) Schematic illustration of connectivity (circle, putative PV+ interneuron; hexagons, stellate cells). Data are from (75). (D) Recurrent inhibition in the hippocampal CA1 region. (Top) Schematic illustration of the stimulation procedure. (Bottom) Traces illustrating IPSPs simultaneously recorded in the soma and the dendrite of a CA1 pyramidal neuron. The slope of rise is higher at the somatic versus the dendritic recording site (inset), indicating that inhibition is generated perisomatically. Data are from (73). (E) Feedback inhibition implements a winner-takes-all mechanism. (Top) Scheme of the neuronal network with external input and feedback inhibition. (Bottom) Plot of the proportion of firing cells (k%) and the proportion of cells that receive excitation within E% of the maximal excitation (E% max). Line styles indicate different distributions of inputs. Note that E% max is relatively independent of the stimulus current. Also note that E% max is d/τm, where d is the delay of disynaptic inhibition and τm is the membrane time constant of the pyramidal cell. Thus, fast signaling in inhibitory interneurons is critically important for the computational properties of the winner-takes-all mechanism. Data are from (76). (F) A continuous attractor network model based on feedback inhibition may produce grid cell activity patterns in excitatory neurons. (Top) Distribution of E-I and I-E synaptic conductances in the model (E, excitatory; I, inhibitory). (Bottom) Pseudocolor representation of simulated activity of E cells in two-dimensional space. Cells receive background activation, theta-modulated input, velocity-modulated input, and place-cell input from the hippocampus. Synaptic output is shifted according to the direction of preferred movement. Data are from (81).

  6. Fig. 6 The role of PV+ interneurons in complex animal behavior.

    (A) Activity of PV+ interneurons in the hippocampal CA1 region of freely moving rats. (Top) Firing of a PV+ interneuron during SWRs. Upper trace, local field potential (filtered 130–230 Hz); lower trace, unit activity from a PV+ interneuron. Asterisks indicate ripples. (Bottom) Summary bar graph indicating the mean action potential frequency. Note that the action potential frequency of PV+ interneurons is >100 Hz during SWRs. Error bars denote SEM. Data are from (87). (B) Spatial firing of PV+ interneurons and principal neurons. (Top) Place cell firing of hippocampal neurons; (bottom) grid cell firing of entorhinal cortex neurons. Warm colors indicate high action potential frequency. Note that putative PV+ interneurons (PV+ INs) have broader spatial fields than principal neurons (PNs). Data are from (82, 91). (C) Orientation selectivity (left) and contrast sensitivity (right) of layer two and three pyramidal neurons in the primary visual cortex. Top graphs, PV+ interneuron; bottom graphs, principal neuron. Note the broad orientation specificity and shallow contrast sensitivity of PV+ interneurons in comparison to pyramidal neurons. V1, primary visual cortex; OSI, orientation selectivity index. Error bars indicate SEM. Data are from (95). (D) PV+ interneuron activity regulates place field shape and phase precession in headfixed mice running on a treadmill belt. (Top) Spike frequency of CA1 pyramidal neurons versus location. (Bottom) Theta phase of action potentials versus location. Blue, control data; red, data after light pulses, leading to halorhodopsin-mediated inhibition of PV+ interneurons. Data are from (92). (E) PV+ interneuron activity regulates the gain of orientation-selective visual responses. Tuning curves of pyramidal neuron activity in the primary visual cortex during a visual stimulus (drifting grating) are shown. Black, control conditions; red, after activation of PV+ interneurons with channelrhodopsin; green, after suppression of PV+ interneurons with archaerhodopsin. Error bars indicate bootstrapped 95% confidence intervals. Data are from (95). (F) Role of PV+ interneurons in associative auditory fear conditioning. (Left, top) Activity of PV+ interneuron in the auditory cortex during unconditional stimuli (foot shocks, cell-attached recording). (Left, bottom) Summary of activity changes of PV+ interneurons during foot shocks (z score). (Right) Behavioral freezing of the animal in baseline conditions and in the presence of the conditioned stimulus (CS+, tone). Black, sham control; blue, with optogenetic stimulation of PV+ interneurons; red, after reconditioning without optogenetic stimulation. Data are from (104). AC, auditory cortex. Error bars, SEM; asterisks, significance (P < 0.001).