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After over seven decades of neuroscience research, it is now well established that [gamma]-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Kresimir Krnjevic (1927-2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjevic was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology. Key words: Kresimir Krnjevic, In memoriam. Apres plus de sept decennies de recherche en neurosciences, il est maintenant bien etabli que l'acide y- aminobutyrique (GABA) est le principal neurotransmetteur inhibiteur dans le cerveau. Dans cet article en hommage a Kresimir Krnjevic (1927-2021), pionnier et chef de file en neurosciences, nous soulignons brievement ses contributions fondamentales a l'etablissement du GABA comme neurotransmetteur inhibiteur dans le cerveau, de meme que nos interactions personnelles avec lui. A noter qu'entre 1972 et 1978, le Dr Krnjevic a ete un editeur en chef hautement repute de la Revue canadienne de physiologic et de pharmacologic. [Traduit par la Redaction] Mots-cles: Kresimir Krnjevic, In memoriam., Introduction GABA ([gamma]-aminobutyric acid) is a key player in neuronal inhibition in the brain and its roles are far beyond inhibition stricto sensu. GABAergic currents are involved in the generation [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2010.08.005 Byline: Yehezkel Ben-Ari (1), Nicholas C. Spitzer (2) Abstract: Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and constitute presymptomatic signatures of neurological disorders when they go awry. Author Affiliation: (1) Institut de Neurobiologie de la Mediterranee (INMED), Institut National de la Sante et de la Recherche Medicale (INSERM) Unite 901, Parc Scientifique de Luminy, BP 13, 13273 Marseille CEDEX 09, France (2) Neurobiology Section, Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093, USA

During brain development cells divide, differentiate and migrate to their assigned targets to form synapses and active cell assemblies. This sequence is controlled both by genetic programs and environmental factors. Alterations of this sequence by mutations or environmental insults leads to the formation of misconnected circuits endowed with a 'pre-symptomatic signature'. I propose here that early- and late-onset neurological disorders as diverse as infantile epilepsies, mental retardation, dyslexia or, in certain conditions, even Huntington's and Alzheimer's disease might be, in part, born at early developmental stages before symptoms appear. The core of this working hypothesis is that imaging or non-invasive recordings might unravel signatures of disorders to come, thereby permitting earlier diagnosis and potential treatment of neurological disorders.

Byline: Jerome Epsztein (INMED (Institut de Neurobiologie de la Mediterranee), INSERM (Institut National de la Sante et de la Recherche Medicale Unite 29), and Universite de La Mediterranee, Marseille Cedex, [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2006.06.001 Byline: Michel Le Van Quyen (a), Ilgam Khalilov (b), Yehezkel Ben-Ari (b) Abstract: Adult brain networks generate a wide range of oscillations. Some of these are behaviourally relevant, whereas others occur during seizures and other pathological conditions. This raises the question of how physiological oscillations differ from pathogenic ones. In this review, this issue is discussed from a developmental standpoint. Indeed, both epileptic and physiological high-frequency oscillations (HFOs) appear progressively during maturation, and it is therefore possible to determine how this program corresponds to maturation of the neuronal populations that generate these oscillations. We review here important differences in the development of neuronal populations that might contribute to their different oscillatory properties. In particular, at an early stage, the density of glutamatergic synapses is too low for physiological HFOs but an additional drive can be provided by excitatory GABA, triggering epileptic HFOs and the cascades involved in long-lasting epileptogenic transformations. This review is part of the INMED/TINS special issue Nature and nurture in brain development and neurological disorders, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/). Author Affiliation: (a) LENA-CNRS UPR640, Universite Pierre et Marie Curie, HA[acute accent]pital de la SalpA*triere, 47 Bd de l'HA[acute accent]pital, 75651 Paris Cedex 13, France (b) INMED-INSERM U29, 163 Route de Luminy, 13273 Marseille Cedex 09, France

Adult brain networks generate a wide range of oscillations. Some of these are behaviourally relevant, whereas others occur during seizures and other pathological conditions. This raises the question of how physiological oscillations differ from pathogenic ones. In this review, this issue is discussed from a developmental standpoint. Indeed, both epileptic and physiological high-frequency oscillations (HFOs) appear progressively during maturation, and it is therefore possible to determine how this program corresponds to maturation of the neuronal populations that generate these oscillations. We review here important differences in the development of neuronal populations that might contribute to their different oscillatory properties. In particular, at an early stage, the density of glutamatergic synapses is too low for physiological HFOs but an additional drive can be provided by excitatory GABA, triggering epileptic HFOs and the cascades involved in long-lasting epileptogenic transformations. This review is part of the INMED/TINS special issue Nature and nurture in brain development and neurological disorders, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

During brain development, transmitter-gated receptors are operative before synapse formation, suggesting that their action is not restricted to synaptic transmission. GABA, which is the principal excitatory transmitter in the developing brain, acts as an epigenetic factor to control processes including cell proliferation, neuroblast migration and dendritic maturation. These effects appear to be mediated through a paracrine, diffuse, non-synaptic mode of action that precedes the more focused, rapid mode of operation characteristic of synaptic connections. This sequential operation implies that GABA is used as an informative agent but in a unique context at an early developmental stage. This sequence also implies that by altering these effects, drugs acting on the GABA system could be pathogenic during pregnancy.

Because blocking GABAergic neurotransmission in control tissue generates seizures and because GABA boosters control epilepsy in many patients, studies on epilepsies have been dominated by the axiom that seizures are generated by a failure of GABA-mediated inhibition. However, GABAergic interneurons and synapses are heterogeneous and have many roles that go beyond the straightforward concept of 'inhibition of the target'. Operation of such a diversified system cannot be ascribed to a single mechanism. In epileptic tissue, GABAergic networks undergo complex rewiring at the anatomical, physiological and functional levels; GABAergic synapses are still operative but show unique features, including excitatory effects. Therefore, inhibition is not a uniform notion and the concept of 'failure' of inhibition in epilepsies must be reassessed. Seizures are not generated in a normal circuit in which GABAmediated inhibition is simply impaired, but in a profoundly rewired network in which several properties of GABA function are altered. This review is part of the TINS Interneuron Diversity series.