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

Background Neuronal networks in the brain include glutamatergic principal neurons and GABAergic interneurons (GABA, γ-aminobutyric acid). The latter may be a minority cell type, but they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function is impaired, higher brain function can be damaged and seizures may result. The fast-spiking, parvalbumin-positive interneurons (PV+ interneurons) are readily characterized and, consequently, have been adopted as a research model for systematic and quantitative investigations. These cells contribute to feedback and feedforward inhibition and are critically involved in the generation of network oscillations. They can convert an excitatory input signal into an inhibitory output signal within a millisecond, but it is unclear how these signaling properties are implemented at the molecular and cellular levels, nor how PV+ interneurons shape complex network functions. PV+ interneurons: from cellular design to microcircuit function. (A) Morphological properties of PV+ interneurons. Reconstruction of a PV+ basket cell in the CA1 region of the hippocampus previously recorded in a freely moving rat. Soma and dendrites are shown in black; axon is depicted in red. CA1, cornu ammonis region 1; SR, stratum radiatum; SP, stratum pyramidale; SO, stratum oriens. For details, see Fig. 1B. (B) Subcellular physiology of PV+ interneurons. Simultaneous recording from the soma and dendrite of a PV+ interneuron in the dentate gyrus (DG) in vitro. (Bottom left) Somatic recording pipette (used for fluorescent dye labeling); (top right) dendritic recording pipette. For details, see Fig. 2A. (C) Network function of PV+ interneurons. (Top) Place cell firing of hippocampal neurons; (bottom) grid cell firing of entorhinal cortex (EC) neurons in vivo. Warm colors indicate high action potential frequency. Putative PV+ interneurons (PV+ INs) have broader spatial fields than principal neurons (PNs). For details, see Fig. 6B. Advances Recent work sheds light on the subcellular signaling properties of PV+ interneurons. PV+ cells show a high degree of polarity. The weakly excitable dendrites allow PV+ interneurons to sample activity in the surrounding network, whereas the highly excitable axons enable analog-to-digital conversion and fast propagation of the digital signal to a large number of target cells. Additionally, tight coupling of Ca2+ channels and release sensors at GABAergic output synapses increases the efficacy and speed of the inhibitory output. Recent results also provide a better understanding of how PV+ interneurons operate in neuronal networks. Not only are PV+ interneurons involved in basic microcircuit functions, such as feedforward and feedback inhibition or gamma-frequency oscillations, but they also play a role in complex network operations, including expansion of dynamic activity range, pattern separation, modulation of place and grid field shapes, phase precession, and gain modulation of sensory responses. Thus, PV+ interneurons are critically involved in advanced computations in microcircuits and neuronal networks. Outlook Parvalbumin-expressing interneurons may also play a key role in numerous brain diseases. These include epilepsy, but also complex psychiatric diseases such as schizophrenia. Thus, PV+ interneurons may become important therapeutic targets in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will have a chance to successfully use PV+ interneurons for therapeutic purposes. A central player in brain computation A small subgroup of nerve cells plays a central role in information processing in the brain. Hu et al. review our present knowledge about the specific makeup of these neurons. Specifically, the individual properties of the molecules, their distribution within the cell, and the anatomy of the cells themselves are described. This information helps to explain why these neurons are so important for the function of microcircuits in the brain, as well as the behavior of the organism. This detailed level of understanding will become relevant as these cells become future targets for the treatment of neurological diseases. Science, this issue p. 10.1126/science.1255263 The success story of fast-spiking, parvalbumin-positive (PV+) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV+ interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the “small world” of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV+ interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV+ interneurons for therapeutic purposes.