Oxytocin and Vasopressin, and the GABA Developmental Shift During Labor and Birth: Friends or Foes?

Oxytocin (OT) and vasopressin (AVP) are usually associated with sociability and reduced stress for the former and antidiuretic agent associated with severe stress and pathological conditions for the latter. Both OT and AVP play major roles during labor and birth. Recent contradictory studies suggest that they might exert different roles on the GABA excitatory/inhibitory developmental shift. We reported (Tyzio et al., 2006) that at birth, OT exerts a neuro-protective action mediated by an abrupt reduction of intracellular chloride levels ([Cl−]i) that are high in utero, reinforcing GABAergic inhibition and modulating the generation of the first synchronized patterns of cortical networks. This reduction of [Cl−]i levels is abolished in rodent models of Fragile X Syndrome and Autism Spectrum Disorders, and its restoration attenuates the severity of the pathological sequels, stressing the importance of the shift at birth (Tyzio et al., 2014). In contrast, Kaila and co-workers (Spoljaric et al., 2017) reported excitatory GABA actions before and after birth that are modulated by AVP but not by OT, challenging both the developmental shift and the roles of OT. Here, I analyze the differences between these studies and suggest that the ratio AVP/OT like that of excitatory/inhibitory GABA depend on stress and pathological conditions

Endogenous neurotrophins are required for the induction of GABAergic long-term potentiation in the neonatal rat hippocampus.

International audienceIn the developing rat hippocampus, GABAergic synapses undergo a Ca2+-dependent long-term potentiation (LTP(GABA-A)); this form of synaptic plasticity is induced in CA3 pyramidal neurons by delivering repetitive depolarizing pulses (DPs) to the recorded neuron, and it is expressed as a long-lasting increase in the frequency and amplitude of spontaneous GABA(A) receptor-mediated postsynaptic currents. In the present study, we examined the role of endogenous tropomyosin-related kinase receptor B (TrkB) receptor ligands and associated protein tyrosine kinases (PTKs) in the induction of LTP(GABA-A). The application of Lavendustin A, a broad spectrum PTK inhibitor, blocked the induction of LTP(GABA-A), whereas Lavendustin B, its inactive form, had no effect. Moreover, k-252a and k-252b, two alkaloids that inhibit the kinase activity of the Trk receptor family, also prevented the induction of LTP(GABA-A). On hippocampal slices incubated with the soluble form of TrkB receptor IgG (TrkB-IgG), which prevents the activation of TrkB receptors by endogenous ligands, DPs failed to induce LTP(GABA-A), whereas the incubation with TrkA-IgG or TrkC-IgG had no such effect. Altogether, these data indicate that endogenous TrkB ligands and associated PTK activity are necessary for the induction of GABAergic LTP in the developing rat hippocampus

Paradoxical anti-epileptic effects of a GluR5 agonist of kainate receptors.

International audienceKainate generates in adult hippocampal neurons a seizure but also a massive excitation of interneurons and a dramatic increase of the inhibitory drive that impinges on principal cells. This "overinhibition" is largely mediated by GluR5-containing kainate receptors that are enriched on interneurons. Here, using the neonatal intact hippocampus in vitro and the triple chamber, we first show that this mechanism is fully operative in neonatal neurons. We then report that application to one hippocampus of (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid-a relatively selective agonist of GluR5 containing kainate receptors-depresses the propagation of seizure generated in the opposite hippocampus by a convulsive agent. We conclude that the selective excitation of interneurons by GluR5-containing kainate receptor agonists opens a new therapeutic approach for the epilepsies

Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?

The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl–)I) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl–)I with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl–)I levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease

Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat.

International audienceBACKGROUND AND PURPOSE: The contribution of inflammatory response to the pathogenesis of ischemic lesions in the neonate is still uncertain. This study described the chronological sequence of inflammatory changes that follow cerebral ischemia with reperfusion in the neonatal P7 rat. METHODS: P7 rats underwent left middle cerebral artery electrocoagulation associated with 1-hour left common carotid artery occlusion. The spatiotemporal pattern of cellular responses was characterized immunocytochemically with the use of antibodies against rat endogenous immunoglobulins to visualize the area of the breakdown of the blood-brain barrier. Infiltration of neutrophils and T lymphocytes was demonstrated by antibodies against myeloperoxidase and a pan-T cell marker, respectively. Antibodies ED1 and OX-42 were applied to identify microglial cells and macrophages. The response of astrocytes was shown with antibodies against glial fibrillary acidic protein. Cell survival was assessed by Bcl-2 expression. Cell death was demonstrated by DNA fragmentation with the use of the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) assay and Bax immunodetection. RESULTS: Endogenous immunoglobulin extravasation through the blood-brain barrier occurred at 2 hours of recirculation and persisted until 1 month after ischemia. Neutrophil infiltration began at 24 hours and peaked at 72 to 96 hours (30+/-3.4 neutrophils per 0.3 mm(2); P<0.0001), then disappeared at 14 days after ischemia. T cells were observed between 24 and 96 hours of reperfusion. Resident microglia-macrophages exhibited morphological remnants and expressed the cell death inhibitor Bcl-2 at 24 hours of recirculation. They became numerous within the next 48 hours and peaked at 7 days after ischemia. Phenotypic changes of resident astrocytes were apparent at 24 hours, and they proliferated between 48 hours and 7 days after ischemia. Progressively inflammatory cells showed DNA fragmentation and the cell death activator Bax expression. Cell elimination continued until there was a complete disappearance of the frontoparietal cortex. CONCLUSIONS: These data demonstrate that perinatal ischemia with reperfusion triggers acute inflammatory responses with granulocytic cell infiltration, which may be involved in accelerating the destructive processes

Rapid cortical oscillations and early motor activity in premature human neonate.

International audienceDelta-brush is the dominant pattern of rapid oscillatory activity (8-25 Hz) in the human cortex during the third trimester of gestation. Here, we studied the relationship between delta-brushes in the somatosensory cortex and spontaneous movements of premature human neonates of 29-31 weeks postconceptional age using a combination of scalp electroencephalography and monitoring of motor activity. We found that sporadic hand and foot movements heralded the appearance of delta-brushes in the corresponding areas of the cortex (lateral and medial regions of the contralateral central cortex, respectively). Direct hand and foot stimulation also reliably evoked delta-brushes in the same areas. These results suggest that sensory feedback from spontaneous fetal movements triggers delta-brush oscillations in the central cortex in a somatotopic manner. We propose that in the human fetus in utero, before the brain starts to receive elaborated sensory input from the external world, spontaneous fetal movements provide sensory stimulation and drive delta-brush oscillations in the developing somatosensory cortex contributing to the formation of cortical body maps

A Parturition-Associated Nonsynaptic Coherent Activity Pattern in the Developing Hippocampus

SummaryCorrelated neuronal activity is instrumental in the formation of networks, but its emergence during maturation is poorly understood. We have used multibeam two-photon calcium microscopy combined with targeted electrophysiological recordings in order to determine the development of population coherence from embryonic to postnatal stages in the hippocampus. At embryonic stages (E16–E19), synchronized activity is absent, and neurons are intrinsically active and generate L-type channel-mediated calcium spikes. At birth, small cell assemblies coupled by gap junctions spontaneously generate synchronous nonsynaptic calcium plateaus associated to recurrent burst discharges. The emergence of coherent calcium plateaus at birth is controlled by oxytocin, a maternal hormone initiating labour, and progressively shut down a few days later by the synapse-driven giant depolarizing potentials (GDPs) that synchronize the entire network. Therefore, in the developing hippocampus, delivery is an important signal that triggers the first coherent activity pattern, which is silenced by the emergence of synaptic transmission

A Randomised Controlled Trial of Bumetanide in the Treatment of Autism in Children

Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study, we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3–11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90−D0; P<0.004 treated vs placebo), Clinical Global Impressions (P<0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean±s.d.; n=9) were removed (Wilcoxon test: P-value=0.031; Student's t-test: P-value=0.017). Side effects were restricted to an occasional mild hypokalaemia $(3.0–3.5 mM l^{−1} K^{+})$ that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al., submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment

Animal Intelligence

So far as evolution is concerned, it really matters little\u27 at what point intelligence appears. Intelligence proper includes the reasoning power as its chief and distinguishing characteristic. Facts regarded as proving a degree of this power in animals were reviewed in detail, and shown to be susceptible of a lower interpretation in harmony with the general phenomena of animal life

an international symposium held in Pavia on July 4th, 2014

New progresses into the molecular and cellular mechanisms of autism spectrum disorders (ASDs) have been discussed in 1 day international symposium held in Pavia (Italy) on July 4th, 2014 entitled “synapses as therapeutic targets for autism spectrum disorders” (satellite of the FENS Forum for Neuroscience, Milan, 2014). In particular, world experts in the field have highlighted how animal models of ASDs have greatly advanced our understanding of the molecular pathways involved in synaptic dysfunction leading sometimes to “synaptic clinical trials” in children