Suppression of GABAergic transmission in the spinal dorsal horn induces pain-related behavior in a chicken model of spina bifida
Md. Sakirul Islam KhanHiroaki NabekaFarzana IslamTetsuya ShimokawaShouichiro SaitoTetsuya TachibanaSeiji Matsuda
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Abstract Spina bifida aperta (SBA), one of the most common congenital malformations, causes various neurological disorders. Pain is a common complaint of patients with SBA. However, little is known about the neuropathology of SBA-related pain. Because loss of γ-aminobutyric acid (GABA)ergic neurons in the spinal cord dorsal horn is associated with pain, we hypothesized the existence of cross-talk between SBA-related pain and alterations in GABAergic transmission in the spinal cord. Therefore, we investigated the kinetics of GABAergic transmission in the spinal cord dorsal horn in a chicken model of SBA. Neonatal chicks with SBA exhibited various pain-like behaviors, such as an increased number of vocalizations with elevated intensity (loudness) and frequency (pitch), reduced mobility, difficulty with locomotion, and escape reactions. Furthermore, the chicks with SBA did not respond to standard toe-pinching, indicating disruption of the spinal cord sensorimotor networks. These behavioral observations were concomitant with loss of GABAergic transmission in the spinal cord dorsal horn. We also found apoptosis of GABAergic neurons in the superficial dorsal horn in the early neonatal period, although cellular abnormalization and propagation of neurodegenerative signals were evident at middle to advanced gestational stages. In conclusion, ablation of GABAergic neurons induced alterations in spinal cord neuronal networks, providing novel insights into the pathophysiology of SBA-related pain-like complications.Numerous neurological disorders are caused by a dysfunction of the GABAergic system that impairs or either stimulates its inhibitory action over its neuronal targets. Pharmacological drugs have generally been proved very effective in restoring its normal function, but their lack of any sort of spatial or cell type specificity has created some limitations in their use. In the last decades, cell-based therapies using GABAergic neuronal grafts have emerged as a promising treatment, since they may restore the lost equilibrium by cellular replacement of the missing/altered inhibitory neurons or modulating the hyperactive excitatory system. In particular, the discovery that embryonic ganglionic eminence-derived GABAergic precursors are able to disperse and integrate in large areas of the host tissue after grafting has provided a strong rationale for exploiting their use for the treatment of diseased brains. GABAergic neuronal transplantation not only is efficacious to restore normal GABAergic activities but can also trigger or sustain high neuronal plasticity by promoting the general reorganization of local neuronal circuits adding new synaptic connections. These results cast new light on dynamics and plasticity of adult neuronal assemblies and their associated functions disclosing new therapeutic opportunities for the near future.
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GABAergic interneurons powerfully control the function of cortical networks. In addition, they strongly regulate cortical development by modulating several cellular processes such as neuronal proliferation, migration, differentiation and connectivity. Not surprisingly, aberrant development of GABAergic circuits has been implicated in many neurodevelopmental disorders including schizophrenia, autism and Tourette's syndrome. Unfortunately, efforts directed towards the comprehension of the mechanisms regulating GABAergic circuits formation and function have been impaired by the strikingly heterogeneity, both at the morphological and functional level, of GABAergic interneurons. Recent technical advances, including the improvement of interneurons-specific labelling techniques, have started to reveal the basic principles underlying this process. This review summarizes recent findings on the mechanisms underlying the construction of GABAergic circuits in the cortex, with a particular focus on potential implications for brain diseases with neurodevelopmental origin.
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The function of the cerebral cortex requires the coordinated action of two major neuronal subtypes, the glutamatergic projection neurons and the GABAergic interneurons. Although, in terms of numbers, GABAergic interneurons represent a minor cell population compared to glutamatergic neurons in the neocortex, they play an important role in modulating network dynamics of neocortical circuits. Indeed, GABAergic interneurons have been shown to control neuronal excitability and integration, and they have been implicated in the generation of temporal synchrony and oscillatory behavior among networks of pyramidal neurons. Such oscillations within and across neural systems are believed to serve various complex functions, such as perception, movement initiation, and memory. Recently, the development of GABAergic inhibition has been shown to be a key determinant for critical period plasticity of cortical circuits. Critical periods represent heightened epochs of brain plasticity, during which experience can produce permanent, large-scale changes in neuronal circuits. Experience-dependent refinement of neural circuits has been described in many regions within the CNS, suggesting it is a fundamental mechanism for normal vertebrate CNS development. By regulating the onset and closure of critical periods, GABAergic interneurons may influence how experience shapes brain wiring during early life and adolescence.
Considering the multifaceted role played by GABAergic cells in the development, function, and plasticity of neural circuits, it is not surprising that alterations in the development of GABAergic circuits per se have been implicated in various neurodevelopmental and psychiatric disorders such as schizophrenia, autism, and epilepsy. However, how modification of GABAergic circuit development contributes to specific pathologies is largely unknown. Furthermore, GABA mimetic drugs, such as benzodiazepines and certain antiepileptic drugs, are widely used in clinical practice, but whether and to what extent these drugs cause deleterious effect on the developing brain is still not clear. A better comprehension of the mechanisms underlying the development and plasticity of GABAergic interneurons will likely indicate which cellular substrates might be affected in neurodevelopmental disorders. At the same time, identifying the genetics variants implicated in these disorders may generate major new insights into the normal and pathological function of GABAergic circuits.
Our understanding of GABAergic interneurons function is challenged by their startling heterogeneity; indeed, different subtypes of interneurons display distinct morphology, physiological properties, connectivity patterns, and biochemical constituents. Recent technical advances have significantly accelerated progress in this field. In particular, the development of genetic strategies based on interneuron cell type-specific promoters and fluorescent protein reporters has allowed efficient high-resolution labelling of specific GABAergic interneuron classes in intact or semi-intact tissues, such as organotypic brain cultures.
Contributions to this special issue of provide an overview of recent discoveries in the field of GABAergic circuit development and related brain disorders. The genetic program for the construction of cortical GABAergic network is initiated early during brain development, and it orchestrates cell type specification, migration, and some aspects of synaptic connectivity. On the other hand, the establishment of mature patterns of GABAergic innervation and inhibitory transmission is not achieved until adolescence and is profoundly influenced by neuronal activity and experience. E. Rossignol describes the tightly controlled genetic cascades that determine the great diversity of cortical GABAergic interneurons and how dysfunctions in genes important for their generation, specification, and maturation might contribute to various neurodevelopmental disorders. B. Chattopadhyaya describes the molecular mechanisms underlying the activity-dependent maturation of GABAergic innervation in the postnatal brain.
Several articles in the special issue have investigated the evidence linking dysfunction in GABAergic signaling and plasticity to specific neurodevelopment disorders, such as autism (R. Pizzarelli and E. Cherubini, J. LeBlanc and M. Fagiolini, L. Baroncelli et al.), schizophrenia (G. Gonzales-Burgos et al.), and epilepsy (Griggs and Galanopoulou). The developmental role of GABAergic circuits is not limited either to the brain or to the developmental phase. A. E. Allain et al. discuss the role of GABA and GABAergic receptors in motoneuron development and in immature hypoglossal motoneurons of the spastic mouse, a model of human hyperekplexic syndrome. B. Imbrosci and T. Mittman describe the response of the GABAergic system to cortical injuries in the adult and how this response could be manipulated to help the functional recovery of patients.
In the last decades, cell-based therapies using GABAergic neuronal grafts have emerged as a promising treatment, since they may restore the lost equilibrium by cellular replacement of the missing/altered inhibitory neurons or modulating the hyperactive excitatory system. Advances in this field are reviewed by V. Broccoli and M. Dolado.
It is becoming increasingly clear that the strength of GABAergic synaptic transmission is dynamic. R. Wright et al. review some of the sophisticated ways in which GABA-A receptor driving force can vary within neuronal circuits. P. Mendez and A. Bacci discuss the plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission, while P. Wenner describes new insight into the mechanisms of GABAergic homeostatis in developing motor networks. Finally, A. Ludwig et al. provide evidence that the trophin nurturin is implicated in the developmental regulation of the cotransporter KCC2, a key molecular player in the establishment of the chloride-gradient, which in turn regulates the strength of GABAergic transmission.
We hope that this special issue will serve to emphasize the new technical and conceptual advances in the field of GABAergic circuits development and to highlight the importance of this network for neurological disorders.
Graziella Di Cristo
Tommaso Pizzorusso
Laura Cancedda
Evelyne Sernagor
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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.
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GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system.
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GABA is a key mediator of neural activity in the mammalian central nervous system, and a diverse set of GABAergic neurons utilize GABA as a transmitter. It has been widely accepted that GABAergic neurons typically serve as interneurons while glutamatergic principal cells send excitatory signals to remote areas. In general, glutamatergic projection neurons monosynaptically innervate both principal cells and local GABAergic interneurons in each target area, and these GABAergic cells play a vital role in modulation of the activity of principal cells. The formation and recall of sensory, motor and cognitive representations require coordinated fast communication among multiple areas of the cerebral cortex, which are thought to be mostly mediated by glutamatergic neurons. However, there is an increasing body of evidence showing that specific subpopulations of cortical GABAergic neurons send long-range axonal projections to subcortical and other cortical areas. In particular, a variety of GABAergic neurons in the hippocampus project to neighboring and remote areas. Using anatomical, molecular and electrophysiological approaches, several types of GABAergic projection neurons have been shown to exist in the hippocampus. The target areas of these cells are the subiculum and other retrohippocampal areas, the medial septum and the contralateral dentate gyrus. The long-range GABAergic projection system of the hippocampus may serve to coordinate precisely the multiple activity patterns of widespread cortical cell assemblies in different brain states and among multiple functionally related areas.
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In recent years, considerable progress has been achieved in deciphering the cellular and network functions of GABAergic transmission in the intact developing brain. First, in vivo studies in non-mammalian and mammalian species confirmed the long-held assumption that GABA acts as a mainly depolarizing neurotransmitter at early developmental stages. At the same time, GABAergic transmission was shown to spatiotemporally constrain spontaneous cortical activity, whereas firm evidence for GABAergic excitation in vivo is currently missing. Second, there is a growing body of evidence indicating that depolarizing GABA may contribute to the activity-dependent refinement of neural circuits. Third, alterations in GABA actions have been causally linked to developmental brain disorders and identified as potential targets of timed prophylactic interventions. In this article, we review these major recent findings and argue that both depolarizing and inhibitory GABA actions may be crucial for physiological brain maturation.
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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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