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About the Authors:
Eric Schnell
* E-mail: [email protected]
Affiliations Portland VA Medical Center, Portland, Oregon, United States of America, OHSU Department of Anesthesiology and Perioperative Medicine, Portland, Oregon, United States of America
AeSoon L. Bensen
Affiliation: The Vollum Institute, Oregon Health & Science University, Portland, Oregon, United States of America
Eric K. Washburn
Affiliation: The Vollum Institute, Oregon Health & Science University, Portland, Oregon, United States of America
Gary L. Westbrook
Affiliation: The Vollum Institute, Oregon Health & Science University, Portland, Oregon, United States of America
Introduction
Adult-generated dentate granule cells have been implicated in learning [1], [2], [3], [4], [5], and dysregulation of neurogenesis has been linked to depression [6], schizophrenia [7], and epilepsy [8]. In animal models, such diseases can disrupt the rate of neurogenesis as well as synapse formation and network integration of newborn neurons [9]. Alterations in synapse formation and in the balance of circuit excitation and inhibition have been increasingly recognized in neurobehavioral disorders [10], [11], suggesting that appropriate integration of neurons is crucial to proper network function. The generation of newborn granule cells in the adult hippocampus provides an interesting model system in this regard, because these cells follow a stereotyped and temporally segregated pattern of synapse formation. As the dendrites of new granule cells increase in complexity and length, GABAergic inputs (weeks 1–2) precede excitatory innervation and spine formation (weeks 3–4) [12], [13], [14]. Eventually, these cells become functionally similar to granule cells generated much earlier in development [15], [16].
Molecular candidates for synapse formation in adult-born neurons have largely been inferred from studies during embryonic development [17]. In particular, the neuroligin (NLG) family of proteins (NLG1-4) [18] is thought to play an important role in synapse formation during early development [19], [20]. However, there are apparent discrepancies between the roles of neuroligins between in vitro and in vivo studies, mostly deduced from studies of the neuroligin-1 isoform. In vitro, neuroligin expression in non-neuronal cells is sufficient to induce functional synaptic connectivity with co-cultured neurons [21], [22], [23], suggesting an instructive role in synapse initiation and assembly. The neuroligin triple knockout mouse has a profound functional synaptic deficit and neonatal mortality [24], but synapse number and morphology are unperturbed, suggesting that neuroligins in vivo act at a stage...