Jonathan Zapata - prix de la Fondation Hugot

Role of Astroglial Connexins in Hippocampal Sharp Wave Ripples

ZapataMulti-electrode arrays -MEA-R

Multi-electrode arrays -MEA-R

A large body of evidence suggests an important role for sleep in memory consolidation. The hippocampus has long been known to play a key role in the formation of memories, including spatial memory. Interestingly, in freely behaving rodents, hippocampal pyramidal neurons selectively discharge when the animal is in a specific location in space: these neurons are referred to as place cells and are thought to form the neural basis for a 'cognitive map' of the environment. Intriguingly, large ensembles of place cells activated during behavior spontaneously replay during sleep the sequence of activation that takes place during exploration. This replay occurs at an accelerated time-scale and is most prominent in slow-wave sleep, during high frequency (~200Hz) oscillations known as Sharp Wave Ripples (SPW-R). This fast timescale is consistent with time windows optimal for induction of long-term potentiation, a candidate molecular mechanism of synaptic plasticity underlying memory. In support of this concept, selective suppression of SPW-R and associated replay impairs performance improvement on a spatial memory task. While this established a clear link between SPW-R and memory consolidation, it remains unclear how this network activity is regulated by learning requirements. Recent data show that spatial learning reinforces the drive for ripples underlying memory consolidation, but how this occurs remains unknown. Candidate mechanisms include increased neuronal excitability and synaptic efficacy, which may result from altered levels of extracellular ions and neuromodulators resulting from dynamic neuroglial interactions. Indeed, astrocytes are now viewed as active elements of the brain circuitry that synchronize neuronal populations and thereby play an important role in behavioral states and cognitive functions. These dynamic neuroglial interactions may involve connexin 30 (Cx30), one of the two main gap-junction subunits expressed in astrocytes, which the host laboratory has recently shown to regulate hippocampal synaptic efficacy. Indeed, Cx30, unlike Cx43, is up-regulated in mice raised in enriched environments, known to enhance learning and memory. In addition, Cx30 elimination alters the reactivity of mice to novel environments and impairs performance in a spatial object recognition task. I found that Cx30 indeed controls the occurrence of SPW-R, since the frequency of ripples ex vivo was significantly decreased in knockout mice for astroglial Cx30. Connexin functions are complex, since they extend beyond the classic intercellular communication and include hemichannel-mediated exchange with the extracellular space, as well as channel-independent functions. Using molecular tools impairing specifically the channel functions of Cx30, I found that Cx30 regulation of hippocampal SPW-R was mediated by its channel function. I also found that Cx30 regulation of SPW-R was associated to an alteration of the excitation-inhibition balance, known to be a key factor in the generation of SPW-R. Finally, I showed that Cx30 sustains performance improvement on a spatial memory task. Altogether, these data, obtained in collaboration with the Zugaro’s group, point to an important role of neuroglial interactions in hippocampal network activity underlying memory consolidation.

Zapata-Enregistrement ex vivo de SPWRs

Enregistrement ex vivo de SPWRs