Role of D-serine in the interaction between dopaminergic and glutamatergic systems in the prefrontal cortex of adult rat

Le cortex préfrontal (PFC) est le principal locus des perturbations dans l’activité des réseaux de neurones chez les schizophrènes. Ces perturbations résultent d’une dérégulation des interactions entre le système dopaminergique et le système glutamatergique dont l’origine demeure inconnue. Il est acquis que les cellules gliales détectent et intègrent les signaux synaptiques, et libèrent différentes substances neuroactives comme la D-sérine. Cet acide aminé est aujourd’hui reconnu comme le coagoniste endogène des récepteurs au glutamate de type NMDA dans de nombreuses aires cérébrales. Mon travail de thèse est centré sur le rôle de la d-sérine dans la transmission synaptique excitatrice glutamatergique dans le PFC du rongeur adulte et dans la gouvernance des interactions entre systèmes glutamatergique et dopaminergiques J’ai tout d’abord montré en utilisant des enregistrements électrophysiologiques sur tranches que la d-sérine est le coagoniste des récepteurs NMDA synaptiques dans les couches V/VI du PFC. Cet acide aminé est synthétisé par les astrocytes et contrôle l’induction de la potentialisation à long terme. D’autre part, j’ai montré que la dopamine exerce un effet biphasique sur l’activité des récepteurs NMDA synaptiques et sur l’excitabilité des neurones pyramidaux des couches V/VI du PFC et ce en contrôlant la libération de d-sérine. Une approche pharmacologique sélective a permis de mettre en évidence le rôle des récepteurs D1 dans les effets potentialisateurs et le rôle des récepteurs D2/D3 dans les effets inhibiteurs de la dopamine. Mon travail démontre que les astrocytes arborent des récepteurs à la dopamine qui contrôlent la libération de la d-sérine.The prefontal cortex (PFC) is the main locus where dysfunctions of neuronal networks are evident in schizophrenia. These dysfunctions are caused by an impairment of cross-talk between dopaminergic and glutamatergic systems whose origin is unknown. It is now accepted that glia detect and integrate synaptic signals and then release many neuroactive substances such as D-serine. This amino acid is now considered to be the endogenous coagonist of the NMDA subtype receptors for glutamate in many brain areas. My PhD work focuses on the functions of d-serine in glutamatergic excitatory synaptic transmission in the PFC of adult rodent and in governing the interactions between dopaminergic and glutamatergic systems. First, using electrophysiological recordings on brain slices, I have shown that d-serine is the coagonist of synaptic NMDA receptors in layers V/VI of PFC. This amino acid is synthesized by glia and is crucial for the induction of long term potentiation. In addition, I have shown that dopamine has a bell-shape effect on the activity of synaptic NMDA receptors and on the excitability of excitatory pyramidal neurons by controlling the release of d-serine. The use of specific pharmacological tools allowed me to show the potentiating effects of dopamine are mediated by D1 receptors whereas the inhibitory effects are due to the activation of D2/D3 receptors. Finally, my work highlights the presence of functional dopaminergic receptors on astrocytes that modulate the release of d-serine in the PFC, thus impacting NMDA receptor activity

Role of D-serine in the interaction between dopaminergic and glutamatergic systems in the prefrontal cortex of adult rat

Le cortex préfrontal (PFC) est le principal locus des perturbations dans l’activité des réseaux de neurones chez les schizophrènes. Ces perturbations résultent d’une dérégulation des interactions entre le système dopaminergique et le système glutamatergique dont l’origine demeure inconnue. Il est acquis que les cellules gliales détectent et intègrent les signaux synaptiques, et libèrent différentes substances neuroactives comme la D-sérine. Cet acide aminé est aujourd’hui reconnu comme le coagoniste endogène des récepteurs au glutamate de type NMDA dans de nombreuses aires cérébrales. Mon travail de thèse est centré sur le rôle de la d-sérine dans la transmission synaptique excitatrice glutamatergique dans le PFC du rongeur adulte et dans la gouvernance des interactions entre systèmes glutamatergique et dopaminergiques J’ai tout d’abord montré en utilisant des enregistrements électrophysiologiques sur tranches que la d-sérine est le coagoniste des récepteurs NMDA synaptiques dans les couches V/VI du PFC. Cet acide aminé est synthétisé par les astrocytes et contrôle l’induction de la potentialisation à long terme. D’autre part, j’ai montré que la dopamine exerce un effet biphasique sur l’activité des récepteurs NMDA synaptiques et sur l’excitabilité des neurones pyramidaux des couches V/VI du PFC et ce en contrôlant la libération de d-sérine. Une approche pharmacologique sélective a permis de mettre en évidence le rôle des récepteurs D1 dans les effets potentialisateurs et le rôle des récepteurs D2/D3 dans les effets inhibiteurs de la dopamine. Mon travail démontre que les astrocytes arborent des récepteurs à la dopamine qui contrôlent la libération de la d-sérine.The prefontal cortex (PFC) is the main locus where dysfunctions of neuronal networks are evident in schizophrenia. These dysfunctions are caused by an impairment of cross-talk between dopaminergic and glutamatergic systems whose origin is unknown. It is now accepted that glia detect and integrate synaptic signals and then release many neuroactive substances such as D-serine. This amino acid is now considered to be the endogenous coagonist of the NMDA subtype receptors for glutamate in many brain areas. My PhD work focuses on the functions of d-serine in glutamatergic excitatory synaptic transmission in the PFC of adult rodent and in governing the interactions between dopaminergic and glutamatergic systems. First, using electrophysiological recordings on brain slices, I have shown that d-serine is the coagonist of synaptic NMDA receptors in layers V/VI of PFC. This amino acid is synthesized by glia and is crucial for the induction of long term potentiation. In addition, I have shown that dopamine has a bell-shape effect on the activity of synaptic NMDA receptors and on the excitability of excitatory pyramidal neurons by controlling the release of d-serine. The use of specific pharmacological tools allowed me to show the potentiating effects of dopamine are mediated by D1 receptors whereas the inhibitory effects are due to the activation of D2/D3 receptors. Finally, my work highlights the presence of functional dopaminergic receptors on astrocytes that modulate the release of d-serine in the PFC, thus impacting NMDA receptor activity

Imagerie des petites voies aériennes dans le cadre de l'asthme

MONTPELLIER-BU Médecine (341722104) / SudocMONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Electrophysiological analysis of the modulation of NMDA-receptors function by D-serine and glycine in the central nervous system

International audienceThe NMDA subtypes of glutamatergic receptors (NMDARs) are unusual in that their activation requires the binding of both glutamate and a co-agonist glycine or D-serine. Whereas glycine was first suggested to play such a role, it was later established that D-serine could serve as an endogenous co-agonist at different central synapses. We still do not know the exact nature of the endogenous co-agonist(s) of NMDARs and the function of the so-called glycine B site in many brain structures. We introduced few years ago the use of enzymes that specifically degrade either D-serine or glycine to decipher the influence of these amino acids on NMDA receptors function. The use of these enzymatic scavengers represents an invaluable technique for neurophysiologists investigating the neuromodulation of the glycine B site in the CNS. Here, we describe the proper way to manipulate these enzymes during electrophysiological recordings in acute brain slices and highlight the experimental tricks

Monitoring of organic contaminants in raw wastewater by targeted and non-targeted screening: an effective tool for assessing urban metabolism

International audienc

Properties of doublecortin expressing neurons in the adult mouse dentate gyrus

The dentate gyrus is a neurogenic zone where neurons continue to be born throughout life, mature and integrate into the local circuitry. In adults, this generation of new neurons is thought to contribute to learning and memory formation. As newborn neurons mature, they undergo a developmental sequence in which different stages of development are marked by expression of different proteins. Doublecortin (DCX) is an early marker that is expressed in immature granule cells that are beginning migration and dendritic growth but is turned off before neurons reach maturity. In the present study, we use a mouse strain in which enhanced green fluorescent protein (EGFP) is expressed under the control of the DCX promoter. We show that these neurons have high input resistances and some cells can discharge trains of action potentials. In mature granule cells, action potentials are followed by a slow afterhyperpolarization that is absent in EGFP-positive neurons. EGFP-positive neurons had a lower spine density than mature neurons and stimulation of either the medial or lateral perforant pathway activated dual component glutamatergic synapses that had both AMPA and NMDA receptors. NMDA receptors present at these synapses had slow kinetics and were blocked by ifenprodil, indicative of high GluN2B subunit content. These results show that EGFP-positive neurons in the DCX-EGFP mice are functionally immature both in their firing properties and excitatory synapses

Intrinsic Properties of EGFP-expressing and Mature Granule Cells.

<p>Histograms of the whole-cell capacitance, resting membrane potential and input resistance demonstrate that EGFP-expressing granule cells (green lines) are typically smaller, more depolarized (though inaccurately measured, see text) and have a higher input resistance than mature dentate gyrus granule cells (DGGC, black lines).</p

Comparison of electrotonic properties of EGFP-positive granule cells and mature dentate gyrus granule cells.

<p>Comparison of electrotonic properties of EGFP-positive granule cells and mature dentate gyrus granule cells.</p

Dendritic Calcium Signaling in EGFP-expressing Granule Cells.

<p>An intracellular calcium rise was elicited by a train of 4 APs at 100 Hz and measured at approximately 20–30 µM from the soma, before the first branch point of the main apical dendrite (white boxes). A. One group of immature EGFP-expressing granule cells, that were unable to fire APs (middle) had no detectable dendritic calcium rise (bottom, average and standard deviation, n = 5) in response to current injections that elicited a change in membrane potential similar in magnitude to an AP. B. More mature looking EGFP-expressing granule cells with sparsely spiny dendrites (top) were able to fire 4 APs (middle) that resulted in a detectable rise in intracellular calcium concentration in the apical dendrite (bottom, average and standard deviation, n = 5). C. Mature granule cells were densely spiny and 4 APs elicited a relatively large rise in dendritic calcium (bottom, average and standard deviation, n = 6). (Inset scale bars are 10 mV and 10 ms).</p

EGFP-expressing neurons do not show a slow afterhyperpolarization.

<p>A. A train of action potentials fired by a mature granule cell (black, top) demonstrating spike-frequency adaptation. Most immature EGFP-expressing granule cells do not fire trains of action potentials in response to suprathreshold current injections. B. Voltage traces elicited in response to a large current injection for EGFP-expressing dentate gyrus granule cells (green) and a mature dentate gyrus granule cell (black), demonstrating the slow AHP is not present in immature granule cells. C. The slow AHP can also be seen in the outward current trace in response to a voltage step to 0 mV (bottom trace) for mature granules cells (black, top) but is absent in the immature cells (green, middle).</p