Jean-Marie Rigo

Beta-carbolines induce apoptotic death of cerebellar granule neurones in culture.

APART from its role in fast inhibitory transmission, only neurotrophic effects have been reported following activation of the GABAA receptor. Here, we show that n-butyl-β-carboline-3-carboxylate and n-methyl-β-carboline-3-carboxamide, which are negative allosteric modulators of the GABAA receptor acting at the benzo-diazepine site, are neurotoxic for cerebellar granule neurones in culture. The β-carboline-induced neuronal death is apoptotic since DNA internucleosomal fragmentation was induced and the neurotoxicity could be prevented by inhibitors of mRNA or protein synthesis. As GABA and benzodiazepine ligands (diazepam and Ro 15–1788) protect cerebellar granule cells against β-carboline-induced toxicity, these data raise the possibility that the interaction between the β-carbolines and the GABAA receptor is the triggering event leading to neuronal apoptosis.

Neurono-Glial Interactions and Neural Plasticity

Publisher Summary This chapter summarizes recent data from laboratory on intercellular messages that are exchanged between neurons and astroglia. Although in several instances, these data have been obtained using embryonic or neonatal material, it is believed that they are relevant to the understanding of brain reaction to injury and neuronal plasticity. Three aspects have been considered in the chapter: (1) neuronal regulation of astroglia proliferation; (2) astroglial regulation of neuronal survival and death; and (3) glial modulation of neuronal neurotransmitter phenotype. Some neurodegenerative disorders could result from a primary astroglial deficit. The chapter points out possible involvement of glia neuronal interactions at some steps of the pathophysiology of these disorders. The essential role of glial cells during development is now a widely accepted concept. There is no reason to believe that glial cells should not play similarly important roles during aging.

In vitro and in vivo modulation of 5-hydroxytryptamine-, thyrotropin-releasing hormone- and calcitonin-gene related peptide-like immunoreactivities in adult rat sensory neurons

In a previous work we have shown that culturing adult rat dorsal root ganglia neurons modifies their neurotransmitter phenotype in such a way that cultured neurons synthesize transmitters that are not found in situ, while several other transmitters are expressed in a much higher percentage of neurons in culture than in situ [Schoenen J. et al. (1989) J. Neurosci. Res. 22, 473-487]. The aim of the present study was to investigate the origin and the nature of the relevant environmental signals that allow this plasticity to be expressed, focusing on three neurotransmitters: 5-hydroxytryptamine, thyrotropin-releasing hormone and calcitonin-gene related peptide. The main results can be summarized as follows: (1) culturing cells in fetal calf serum or on feeder layers of astrocytes, Schwann cells or fibroblasts partially inhibits the serotoninergic phenotype of dorsal root ganglia neurons; (2) in vivo disconnection of dorsal root ganglia from their spinal targets but not from their peripheral or supraspinal targets induces a significant increase of the percentage of 5-hydroxytryptamine- and thyrotropin-releasing hormone-positive neurons in disconnected ganglia; (3) growth factors such as ciliary neuronotrophic factor or basic fibroblast growth factor but not nerve growth factor repress 5-hydroxytryptamine and calcitonin gene-related peptide immunoreactivity in cultured sensory neurons. In conclusion, neurotransmitter gene expression of adult dorsal root ganglia neurons is controlled by complex influences. Our data suggest that thyrotropin-releasing hormone and 5-hydroxytryptamine gene expression are tonically repressed in vivo by factors originating from the spinal segmental level and that growth factors such as ciliary neurotrophic factor or basic fibroblast growth factor could be potential vectors of this repressing effect.

Frequency-dependent modulation of glycine receptor activation recorded from the zebrafish larvae hindbrain

In vertebrates, most glycinergic inhibitory neurons discharge phasically at a relatively low frequency. Such a pattern of glycine liberation from presynaptic terminals may affect the kinetics of post-synaptic glycine receptors. To examine this influence, we have analyzed the behavior of glycine receptors in response to repetitive stimulation at frequencies at which consecutive outside-out currents did not superimpose (0.5-4 Hz). Neurotransmitter release was mimicked on outside-out patches from zebrafish hindbrain Mauthner cells using fast flow application techniques. The amplitude of outside-out currents evoked by short (1 ms) repetitive applications of a saturating concentration (3 mM) of glycine remained unchanged for application frequencies<or=1 Hz. When the application frequency was increased from 1 to 4 Hz, the amplitude of the outside-out currents decreased with time to reach a steady state level. This decrease in current amplitude was larger and occurred faster with increasing application frequencies. Recovery occurred when the stimulation frequency was decreased back to 1 Hz. The recovery time constant was independent on the application frequency. This frequency-dependent inhibition was also observed for non-saturating glycine concentrations. Our results indicate that glycine receptor activity is down-regulated when the stimulation frequency increases to values>1 Hz. Glycine-evoked current simulations using a simple Markov model describing zebrafish glycine receptor kinetic behavior, indicates that this down-regulation of glycine receptor efficacy is due to a progressive accumulation of the receptors in a long lasting desensitization state. Our simulations suggest that this down-regulation can occur even when spontaneous inhibitory currents were generated randomly at a frequency>1 Hz.