Fast-spiking, parvalbumin + GABAergic interneurons: From cellular design to microcircuit function
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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.Keywords:
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The amygdala is a temporal lobe structure that is required for processing emotional information. Polymodal sensory information enters the amygdala at the level of the basolateral amygdala (BLA) and undergoes local processing, after which the behavioral and autonomic responses that accompany emotions are initiated. Two main neuron types are present in the BLA, pyramidal-like principal neurons that use glutamate as their transmitter, and local circuit interneurons that use GABA as their transmitter. Although the properties of principal neurons are known in some detail, very little is known about the properties of BLA interneurons or the local circuits in which they are involved. Using mice in which EGFP (enhanced green fluorescent protein) is expressed under the control of the parvalbumin promoter, we characterized the properties of parvalbumin-positive interneurons in the BLA. By making recordings from interneuron-interneuron and interneuron-principal neuron pairs, we analyzed the intrinsic circuitry of the BLA. We show that parvalbumin-positive interneurons can be divided into four subtypes as defined by their firing properties. Interneurons are electrically coupled in subtype-specific networks and exhibit subtype-specific heterogeneities in their synaptic dynamics and patterns of connectivity. We propose that these properties allow networks of parvalbumin-expressing neurons to perform an array of information-processing tasks within the BLA.
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To reveal functional heterogeneity among GABAergic interneurones in rat neostriatum, we investigated: (1) whether nitric oxide synthase (NOS)- and calretininimmunoreactive cells, like parvalbumin-immunoreactive cells, were also immunoreactive for 67 kD glutamic acid decarboxylase (GAD67 and GABA;(2) whether NOS cells, calretinin cells and parvalbumin cells belonged to separate populations or not. NOS cells, calretinin cells and parvalbumin cells all showed immunoreactivity for GAD67 in colchicine-treated rats. Calretinin cells and parvalbumin cells were also immunoreactive for GABA. Only a few cells (0–3%) showed immunoreactivity for two antigens. These results suggest that the neostriatum has at least three GABAergic interneuronal systems.
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The cognitive phenotype of autism has been correlated with an altered balance of excitation to inhibition in the cerebral cortex, which could result from a change in the number, function, or morphology of GABA-expressing interneurons. The number of GABAergic interneuron subtypes has not been quantified in the autistic cerebral cortex. We classified interneurons into 3 subpopulations based on expression of the calcium-binding proteins parvalbumin, calbindin, or calretinin. We quantified the number of each interneuron subtype in postmortem neocortical tissue from 11 autistic cases and 10 control cases. Prefrontal Brodmann Areas (BA) BA46, BA47, and BA9 in autism and age-matched controls were analyzed by blinded researchers. We show that the number of parvalbumin+ interneurons in these 3 cortical areas—BA46, BA47, and BA9—is significantly reduced in autism compared with controls. The number of calbindin+ and calretinin+ interneurons did not differ in the cortical areas examined. Parvalbumin+ interneurons are fast-spiking cells that synchronize the activity of pyramidal cells through perisomatic and axo-axonic inhibition. The reduced number of parvalbumin+ interneurons could disrupt the balance of excitation/inhibition and alter gamma wave oscillations in the cerebral cortex of autistic subjects. These data will allow development of novel treatments specifically targeting parvalbumin interneurons.
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Inhibitory GABAergic interneurons are important for shaping patterns of activity in neocortical networks. We examined the distributions of inhibitory interneuron subtypes in layer II/III of areas V1 and V2 in 18 genera of anthropoid primates including New World monkeys, Old World monkeys, and hominoids (apes and humans). Interneuron subtypes were identified by immunohistochemical staining for calbindin, calretinin, and parvalbumin and densities were quantified using the optical disector method. In both V1 and V2, calbindin-immunoreactive neuron density decreased disproportionately with decreasing total neuronal density. Thus, V1 and V2 of hominoids were occupied by a smaller percentage of calbindin-immunoreactive interneurons compared to monkeys who have greater overall neuronal densities. At the transition from V1 to V2 across all individuals, we found a tendency for increased percentages of calbindin-immunoreactive multipolar cells and calretinin-immunoreactive interneurons. In addition, parvalbumin-immunoreactive cell soma volumes increased from V1 to V2. These findings suggest that modifications of specific aspects of inhibition might be critical to establishing the receptive field properties that distinguish visual areas. Furthermore, these results show that phylogenetic variation exists in the microcircuitry of visual cortex that could have general implications for sensory processing.
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GABAergic interneurons in the hippocampus provide for local and long-distance coordination of neurons in functionally connected areas. Vasoactive intestinal peptide-expressing (VIP+) interneurons occupy a distinct niche in circuitry as many of them specialize in innervating GABAergic cells, thus providing network disinhibition. In the CA1 hippocampus, VIP+ interneuron-selective cells target local interneurons. Here, we discover a type of VIP+ neuron whose axon innervates CA1 and also projects to the subiculum (VIP-LRPs). VIP-LRPs show specific molecular properties and target interneurons within the CA1 area but both interneurons and pyramidal cells within subiculum. They are interconnected through gap junctions but demonstrate sparse spike coupling in vitro. In awake mice, VIP-LRPs decrease their activity during theta-run epochs and are more active during quiet wakefulness but not coupled to sharp-wave ripples. Together, the data provide evidence for VIP interneuron molecular diversity and functional specialization in controlling cell ensembles along the hippocampo-subicular axis.
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Abstract Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits.
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GABAergic interneurons are inhibitory neurons of the nervous system that play a vital role in neural circuitry and activity. They are so named due to their release of the neurotransmitter gamma-aminobutyric acid (GABA), and occupy different areas of the brain. This review will focus primarily on GABAergic interneurons of the mammalian cerebral cortex from a developmental standpoint. There is a diverse amount of cortical interneuronal subtypes that may be categorized by a number of characteristics; this review will classify them largely by the protein markers they express. The developmental origins of GABAergic interneurons will be discussed, as well as factors that influence the complex migration routes that these interneurons must take in order to ultimately localize in the cerebral cortex where they will integrate with the neural circuitry set in place. This review will also place an emphasis on the transcriptional network of genes that play a role in the specification and maintenance of GABAergic interneuron fate. Gaining an understanding of the different aspects of cortical interneuron development and specification, especially in humans, has many useful clinical applications that may serve to treat various neurological disorders linked to alterations in interneuron populations.
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