In the present study, electrophysiological and behavioral effects of compromised Gama-Aminobutyric Acid (GABAergic) transmission were investigated in adult Rhesus macaque monkeys (N=2). GABAergic transmission was perturbed in the putamen by administration of a GABAa receptor antagonist, gabazine (10 and 500 μM), via a microdialysis-local field potential (MD-LFP) probe. Resultant changes in striatal local field potentials (LFPs) were measured as an assay of synchrony. Gabazine perfusion evoked discrete large amplitude spikes in LFPs in all subjects, and the frequency and shape of individual spikes were concentration-dependent. Pre-treatment with the GABAa receptor agonist, muscimol (100 μM) blocked the gabazine-induced events, confirming a role for GABAa receptors in the effects. Behavioral manifestations of gabazine treatment were observed only at the maximum concentration. Unusual facial movements suggested aberrant electrical activity was propagated from striatum to motor cortex, perhaps via reentrant circuits. These results support a role for GABAergic transmission in segregation of striatal circuits.

Changes in spontaneous spike activities recorded from murine frontal cortex networks grown on substrate-integrated microelectrodes were used to determine the dissociation constant (KB) of three GABAA antagonists. Neuronal networks were treated with fixed concentrations of GABAA antagonists and titrated with muscimol, a GABAA receptor agonist. Muscimol decreased spike activity in a concentration dependent manner with full efficacy (100% spike inhibition) and a 50% inhibitory concentration (IC50) of 0.14 ± 0.05 µM (mean ± SD, n=6). At 10, 20, 40 and 80 µM bicuculline, the muscimol IC50 values were shifted to 4.3 ± 1.8 µM (n=6), 6.8 ± 1.7 µM (n=6), 19.3 ± 3.54 µM (n=10) and 43.5 µM (n=2), respectively (mean ± SD). Muscimol titration in the presence of 10, 20, 40 µM of gabazine resulted in IC50s values of 20.1 (n=2), 37.17 (n=4), and 120.45 (n=2), respectively. In the presence of 20, 80, and 160 µM of TMPP (trimethylolpropane phosphate) the IC50s were 0.86 (n=2), 3.07 (n=3), 6.67 (n=2) µM, respectively. Increasing concentrations of GABAA antagonists shifted agonist log concentration-response curves to the right with identical efficacies, indicating direct competition for the GABAA receptor. A Schild plot analysis with linear regression resulted in slopes of 1.18 ± 0.18, 1.29 ± 0.23 and 1.05 ± 0.03 for bicuculline, gabazine and TMPP, respectively. The potency of antagonists was determined in terms of pA2 values. The pA2 values were 6.63 (gabazine), 6.21 (bicuculline), and 5.4 (TMPP). This suggests that gabazine has a higher binding affinity to the GABAA receptor than bicuculline and TMPP. Hence, using spike rate data obtained from population responses of spontaneously active neuronal networks, it is possible to determine key pharmacological properties of drug-receptor interactions.

Depuis quelques années, l’étude du code neuronal impliqué dans la perception des signaux de communication acoustique est devenue un domaine de recherche considérable. La littérature récente de ce domaine suggère que la discrimination entre ces signaux reposerait plutôt sur une organisation des décharges neuronales en motifs temporels que sur des variations globales de taux de décharge. Ma thèse a eu pour objectif de déterminer dans quelle mesure une régulation des inhibitions corticales peut (i) changer les motifs temporels déclenchés par des vocalisations conspécifiques et hétérospécifiques et (ii) modifier l’information portée par ces motifs sur l’identité des vocalisations. Nous avons enregistré l’activité neuronale dans le cortex auditif de cobayes anesthésiés en 16 sites corticaux lors de la présentation d’un jeu de vocalisations, et avons partiellement bloqué les inhibitions corticales par des applications de Gabazine (4minutes, 10µm). Dans ces conditions, les réponses évoquées sont plus fortes et les motifs temporels plus marqués. L’information mutuelle quantifiée au niveau de chaque site cortical est augmentée mais l’information populationnelle au niveau de l’ensemble des 16 sites enregistrés n’est pas modifiée, un effet qui peut s’expliquer par le fait que la redondance entre les sites corticaux est augmentée. Nous avons ensuite évalué dans quelle mesure une modulation noradrénergique était susceptible de mimer les effets d’un blocage partiel des inhibitions. Bien que les agonistes utilisés (α1, α2 et ) aient tous induit des modifications des réponses évoquées et de la reproductibilité des motifs temporels, aucun d’entre eux n’a induit de changements importants de l’information portée par les réponses neuronales aux vocalisations. En revanche, les effets induits par la phenylephrine, un agoniste α1, sont vraisemblablement sous-tendus par une action sur les inhibitions intra-corticales, ce qui rend plausible l’hypothèse d’une modulation noradrénergique des inhibitions corticales. Il est donc envisageable que l’action coordonnée de plusieurs systèmes neuromodulateurs puisse moduler les inhibitions corticales et ainsi changer la quantité d’information portée par les neurones corticaux sur l’identité des stimuli à discriminer. / Over the last 10 years, the neural code involved in the perception of acoustic communication signals has become a large area of researches. The recent literature suggests that the discrimination between these signals relies more on the temporal organization of neuronal discharges rather than on global changes of firing rate. My PhD thesis aimed at determining to what extent the regulation of cortical inhibition may (i) change the temporal patterns triggered by conspecific and heterospecific vocalizations and (ii) modify the information carried by these patterns on the vocalization identity. Neuronal activity was recorded in the auditory cortex of anesthetized guinea pigs in 16 cortical sites during presentation of a set of vocalizations, and a partial blockage of intra-cortical inhibition was performed by Gabazine application (4 minutes, 10μm). Under these conditions, evoked responses were stronger and the temporal patterns were reinforced. Mutual information quantified at each cortical site was increased but the information computed at the populationnal level did not change, an effect that could be explained by the fact that the redundancy between cortical sites was increased. We then assessed to which extent the noradrenergic modulation can mimic the effects of a partial blockage of inhibitions. Although all the tested drugs modulated both the evoked responses and the spike-timing reliability, none of the noradrenergic agonists used here (α1, α2 and ) induced significant changes in the information carried by neuronal responses. However, the effects induced by phenylephrine, an α1 agonist, seemed to involve an action on the intra-cortical inhibition, which suggests that a noradrenergic modulation of cortical inhibition can operate in the auditory cortex. It is therefore possible to envision that the coordinated action of several neuromodulatory systems modulates cortical inhibition and thus changes the information carried by cortical neurons on the stimuli identity.