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Stéphane Dieudonné

Inhibitory Transmission

Brain function critically depends on the interplay between excitatory and inhibitory transmission. Compromised excitation/inhibition balance leads to pathological states, such as epilepsy and hyperekplexia, or to modified brain states, as illustrated by the action of benzodiazepines and general anesthetics. Our aim is to understand the contribution of inhibitory neurons to the stability of brain function through the dissection of elementary processes such as activity-dependent neurotransmitter release, single neuron computation, oscillatory synchronization of neuronal populations, gain control in brain microcircuits and sensory-motor gating. To this end, we apply a multi-level approach ranging from the molecular dissection of inhibitory vesicle filling, to the behavioral assessment of in-vivo optogenetic stimulations of specific inhibitory neurons.

The neurotransmitters glycine and GABA mediate fast inhibitory synaptic transmission. We have shown that the cytosolic content of inhibitory neurons in glycine or GABA can be exhausted by a few thousand action potentials. Efficient inhibitory transmission thus requires constant neurotransmitter supply and transporter-mediated uptake plays a key role maintaining vesicle filling and the strength of inhibition during sustained activity. Our data further suggest a tight interplay between this transmitter supply cycle and the vesicle exo/endocytic cycle, which limits futile cycles. We are currently exploring the presynaptic mechanisms underlying the activity-dependent metabolic regulation of GABA, glycine and glutamate synaptic release.

In the hindbrain, glycine and GABA can be released by separate neurons or co-released by mixed inhibitory neurons. We have shown that the relative sensitivity of each postsynaptic neuron to GABA or glycine is regulated by clustering of the appropriate complement of GABAA and glycine receptors in front of mixed inhibitory synapses. We now explore how this mechanism may be used to ensure excitation/inhibition balance in face of changing network activity. We have identified homologous subpopulations of inhibitory neurons displaying different ratios of GABA/glycine content. Combining patterned optogenetic stimulation and ultrafast multiphoton monitoring we study how these subpopulations are selectively recruited by activity. We hypothesize that this recruitment, combined with postsynaptic variegation, implements “rate-coding” to “population coding” conversion.
Overall, the impact of inhibitory neurons on network activity is constrained by their activity-dependent recruitment, as determined by the integrative properties of their dendritic arbor and the plasticity of their synaptic inputs. To monitor dendritic activity with high spatiotemporal dynamics, we have developed a random-access multiphoton microscope in collaboration with L. Bourdieu team at IBENS. We have shown in cerebellar Purkinje cells that synaptically triggered calcium signaling is a complex function of presynaptic and postsynaptic activity. We are now studying the link between calcium influx, synaptic integration and plasticity on different timescales.
Finally, inhibitory interneurons are essential components for the genesis of physiologic and pathologic brain oscillations at various frequency bands. During isometric muscular contractions, coherent beta-range (8 - 30 Hz) oscillations are recorded from a number of distant brain structures ranging from motoneurons to the sensorimotor cortex and cerebellum. We have shown how electrical connections between Golgi interneurons of the cerebellum promote the synchronization of their firing at beta frequencies. This population oscillator can resonate with external inputs at preferred frequencies, potentially acting to coordinate sensorimotor processing from distant brain areas. We will use optogenetic tools to probe the role of this cerebellar oscillator in physiological conditions and pathological conditions like essential tremor in vitro and in vivo.

Zampini V, Liu J, Diana M, Maldonado P, Brunel N & Dieudonné S. Mechanisms and functional roles of glutamatergic synapse diversity in a cerebellar circuit. eLife (2016) 5:e15872

Ankri L, Husson Z, Pietrajtis K, Proville R, Léna C, Yarom Y, Dieudonné S & Yoe Uusisaari M. A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity. eLife. (2015) 4:e06262

Giber K, Diana MA, M Plattner V, Dugué GP, Bokor H, Rousseau CV, Maglóczky Z, Havas L, Hangya B, Wildner H, Zeilhofer HU, Dieudonné S & Acsády L A subcortical inhibitory signal for behavioral arrest in the thalamus. Nat Neurosci. (2015) 18:562-568

Otsu Y, Marcaggi P, Feltz A, Isope P, Kollo M, Nusser Z, Mathieu B, Kano M, Tsujita M, Sakimura K & Dieudonné S. Activity-dependent gating of calcium spikes by A-type K+ channels controls climbing fiber signaling in Purkinje cell dendrites. Neuron (2014) 84:137-151

Wang L, Tu P, Bonet L, Aubrey Karin R & Supplisson S. Cytosolic Transmitter Concentration Regulates Vesicle Cycling at Hippocampal GABAergic Terminals. Neuron (2013) 80, 143-158