Major achievements of Lledo's lab

Neurogenesis continues throughout life in the mammalian forebrain, suggesting that recently generated, adult-born neurons contribute to neural plasticity and learning. However, it is still unknown whether newborn neurons display, or not, distinct synaptic properties from their mature counterparts. We have provided such information in a recent study (Nissant et al., Nat. Neurosci. 2009). To explore the functional consequences of adult neurogenesis in the olfactory bulb, we examined whether glutamatergic inputs on olfactory interneurons display synaptic plasticity. We find that, shortly after they differentiate and synaptically integrate, adult-born interneurons exhibit long-term plasticity. Remarkably, the degree of synaptic plasticity fades with maturation of the newcomers. In contrast, when recording pre-existing interneurons, we never observed LTP indicating that recently generated adult-born interneurons play a distinct role in information processing than their more mature counterparts. These results demonstrate that recently generated olfactory neurons and older, preexisting neurons undergo contrasting experience-dependent synaptic changes and support the hypothesis that adult-born neurons are specifically involved in olfactory learning.

It is puzzling to realize that thousands of new cells are generated and reach the olfactory bulb each day. However, a relatively small percentage of those cells persist long enough to become mature cells. At first glance, this seems to be a wasteful process since most of the newly generated neurons die few weeks after birth. On the other hand, elimination of the newborn neurons could represent a necessary accompanying mechanism that follows neuronal recruitment. Thus, it is still unknown whether intense cell death represents an active process by which the host circuit tunes its functioning. For the first time, we provided findings illuminating the function of death of newborn neurons (Mouret et al., J. Neurosci. 2009). In this study, we went further than simply describing the way newborn neurons are eliminated through programmed cell death. We not only showed that the two categories of newborn neurons reaching the bulb respond distinctly to sensory experiences, but we also demonstrated that, in turn, olfactory acuity depends on cell death. This study provided original information on how olfactory acuity in discrimination task is tuned by the turnover of new neurons. This paper represents the first demonstration that both neuronal recruitment and death of the newborn cells are both crucial to adjust the functioning of olfactory bulb network.

In collaboration with the CEA (Fontenay-aux-Roses), we have irradiated adult mice to impair the constitutive bulbar neurogenesis and explore the functional effects on olfactory performance. We found that cell survival depends on the number of newly produced neurons reaching the bulb. When neurogenesis was reduced after irradiation, the survival rate of the newborn neurons was prolonged. Interestingly, we found that long-term olfactory memory was impaired in irradiated animals (Lazarini et al., PlosOne 2009).

We have described the way newborn neurons establish synaptic contacts when arriving into a pre-existing network. We provided both morphological and electrophysiological evidences supporting that synaptic contacts form rapidly (within few day after birth of the new neuron). These contacts mediate simultaneously glutamatergic and GABergic signaling that reach first the soma and the proximal domain of the dendrite of the new neurons and few weeks later at distal portion of the dendrite. This study constitutes the first analysis in which the maturation of synaptic inputs was followed on developing bulbar neurons (Panzanelli et al., J. Neurosci., 2009).

Finally, by introducing and inducing expression of a photo-sensitive protein (Channelrodopsin) in new neurons, we have been able to control their activity with the use of luminescent flashes. We have brought proof that new neurons formed in the adult brain are integrated into preexisting nervous circuits. We have also found that, against all expectations, the number of contacts between young cells and their target cells greatly increased over several months. Together, this work constitutes an essential step in characterizing the functions fulfilled by new neurons. It opens new avenues to investigation for understanding the connectivity between new neurons and their host circuits. This is a crucial step on the way to foreseeing the use of stem cells within the framework of new therapeutic protocols for repairing brain damage, notably in the realm of neurodegenerative diseases.

Link to Activity Report Sheila Harroch'E3 group

Present collaborations:

- Prof. Jochen Herms (Zentrum für Neuropathologie, Ludwig Maximilians Universität, München): Development and advancement in methods and technologies towards the understanding of brain diseases (Supported by the FP7 program- ERA-NET NEURON).

- Prof. Venki Murthy (Harvard University, Depart of Mol & Cell Biology): Mechanisms of Synaptic Transmission and Plasticity in the olfactory bulb (supported by Harvard University and The Phillips Foundation).

Keywords: Adult neurogenesis — Olfactory bulb —Interneurons — Neural stem cells

1. Bardy C, Alonso M, Bouthour W & Lledo P-M (2010). How, when and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb. J. Neurosci. 30, 17023-17034.

2. Nissant A, Bardy C, Katagiri H, Murray K & Lledo P-M (2009). Neurogenesis promotes synaptic plasticity in the adult olfactory bulb. Nat. Neurosci. 12, 728-730

3. Alonso M, Ortega-Perez I, Grubb M, Bourgeois JP, Charneau P & Lledo P-M (2008). A novel neurogenic niche for the adult olfactory bulb. J. Neurosci. 28, 11089-11102.

4. Grubb M, Nissant A, Murray K & Lledo P-M (2008). Functional maturation of the first synapse in olfaction: Development and adult neurogenesis. J. Neurosci. 28, 2919-2932

5. Lagier S, Panzanelli P, Russo R, Sassoè-Pognetto M, Fritschy J-M & Lledo P-M (2007). GABAergic inhibition at dendro-dendritic synapses tunes gamma oscillations in the olfactory bulb. Proc. Natl. Acad. Sci. (USA) 104, 7259-7264.