Granule cells and PGCs are key players in processing odor stimuli in the olfactory bulb (Lledo et al., 2006). These are also the two major populations of interneurons generated during adulthood. Consequently, their functional integration into the pre- existing network in the olfactory bulb has been extensively investigated. Tangentially migrating neuroblasts fi rst express functional GABA receptors, which likely respond to extrasynaptic GABA, and then AMPARs (Bolteus and Bordey, 2004; Carleton et al., 2003). Once they reach the olfactory bulb and start radial migration, some new neurons begin to express NMDARs. Newborn granule cells receive GABAergic and
glutamatergic synapses as soon as they reach the olfactory bulb (Nissant and Pallotto, 2011). Newborn granule cells have been proposed to receive axodendritic synapses from centrifugal fi bres and/or from mitral cell axon collaterals (Whitman and Greer, 2007). These connections appear as early as 10 days post birth in the SEZ and form on proximal dendrites of newborn granule cells. At this stage, they are however unable to fi re action potentials (Whitman and Greer, 2007). At about 21 days post birth begins the formation of the dendrodendritic synapses in the EPL between newborn granule cells and mitral cells. During dendrodendritic synaptogenesis, spine density on adult- born granule cells increases until 28 days after birth, remains stable till 42 days and decreases by 56 days (Whitman and Greer, 2007). This synaptic pruning suggests slow refi nement of interneuron connectivity over the course of several weeks after their arrival in the olfactory bulb. The maturation of the GABAergic input has been suggested to be faster compared to the glutamatergic input (Nissant and Pallotto, 2011). Using channelrhodopsin-encoding lentiviruses, Bardy et al (2010) could demonstrate that newborn granule cells are able to inhibit mitral cells and modulate their activity about two weeks after lentiviral injection in the RMS. However, the probability of revealing a functional contact increases between 4 and 6 weeks after injection (Bardy et al., 2010). This suggests that although the GABAergic output synapses of newborn granule cells are formed quickly, functional maturation of these contacts takes several weeks. Thus, new neurons receive information about the network before contributing to it. This delay in generating output may have evolved to protect the existing circuitry from disruption due to uncontrolled transmitter release. Events occurring during developmental neurogenesis differ signifi cantly where input/output synapses are formed simultaneously with the proximal excitatory input synapses (Kelsch et al., 2008; Lledo et al., 2004). Thus, synaptic integration of adult-generated cells in the olfactory bulb does not seem to recapitulate events occurring during embryonic and postnatal development.
Newborn PGCs, on the other hand, develop voltage-dependent sodium currents and the capacity to fi re action potentials before the appearance of synaptic contacts
(Belluzzi et al., 2003). Periglomerular cells express elaborate dendritic arbors about 2 weeks after birth but mature pedunculated spines appear only at about 6 weeks (Whitman and Greer, 2007). Thus, periglomerular spines appear to mature slower than those of granule cells. This difference in maturation could stem from the intrinsic differences between these cells or the distinct neuronal networks into which they integrate. The PGCs integrate into circuits that undergo constant replacement of afferents (coming from sensory neurons) while newborn granule cells receive inputs from mitral and tufted cells that remain stable throughout the life of the organism (Mizrahi and Katz, 2003).
The functional role of adult neurogenesis in the olfactory bulb has been studied by ablating neurogenesis and its consequent effects at the cellular level as well as on olfactory behaviour. However, the results of these studies are contradictory probably because of the different experimental paradigms used. For example, after cytosine-b-D- arabinofuranoside (ARA-C) infusion for one month mitral cells received fewer inhibitory synapses, displayed reduced frequency of spontaneous inhibitory postsynaptic currents (IPSCs), experienced reduced dendrodendritic inhibition and exhibited decreased synchronized activity (Breton-Provencher et al., 2009). This, at the behavioural level manifested as an increased threshold for detecting odours and a reduction in short-term olfactory memory. However, long-term memory or the ability to discriminate between different odours was unaltered (Breton-Provencher et al., 2009). In contrast, studies have shown that irradiation of the SEZ or ARA-C treatment leads to impairment of long-term associative memory (Lazarini et al., 2009; Sultan et al., 2010). A third study involving genetic ablation of newborn neurons in the SEZ found that although numbers of newly generated granule cells decreased over time, there was no effect on olfactory discrimination in these mice (Imayoshi et al., 2008). However, an earlier study on neural cell adhesion molecule (NCAM)-defi cient mice that display defi cits in migration of neuroblasts to the olfactory bulb, showed a specifi c reduction in the turnover of granule cells which resulted in impairment of discrimination between odours while detection thresholds and short-term olfactory memory were not affected (Gheusi et al., 2000). A
recent study, using optogenetics-based methods, has suggested that adult-born but not postnatal-born granule cell-mediated inhibition of mitral cells is important for learning to discriminate similar odors and retaining the memory for it (Alonso et al., 2012).
Besides odour discrimination and olfactory learning and memory, olfactory neurogenesis has also been implicated in mating and maternal behaviour. Pheromones secreted by dominant males have been shown to increase neurogenesis in the female mice brain, suggesting female preference for dominant males over subordinate males (Mak et al., 2007). Neurogenesis is also markedly increased during pregnancy, stimulated by prolactin which is negated by blocking prolactin signalling. Loss of pup-induced maternal behaviour in prolactin receptor mutant females also suggests a role for neurogenesis in this behaviour (Shingo et al., 2003), although it is unclear if this effect is a direct consequence of new neurons or via another prolactin-mediated mechanism.
In conclusion, it is now clear that adult neurogenesis seems to have an impact on several aspects of olfactory function following sequential synaptic integration of newborn neurons. However, the connectivity of granule cells or PGCs with respect to the different pre- and postsynaptic partners and their location as well as the infl uence of sensory stimulation on newborn neuron connectivity remain unclear. For example, activity-dependent modifi cations have been shown to strongly infl uence the maturation and survival of new neurons. These manipulations are most effective during a critical time window of 2-4 weeks after generation (Nissant and Pallotto, 2011). This is the exact time during which these cells begin to receive glutamatergic synaptic inputs. Moreover, proximal glutamatergic inputs onto newborn granule cells are able to support LTP, which disappears as they mature and is no longer detectable 3 months after birth (Nissant and Pallotto, 2011). It would be interesting to know the identity of these inputs and the particular contribution of various synaptic inputs that regulate the addition of new neurons to the olfactory bulb and thereby its effect on olfaction.