It is now well established that the mammalian brain has the capacity to produce new neurons into adulthood. One such region that provides the proper milieu to sustain progenitor cells and is permissive to neuronal fate determination is located in the dentate gyrus of the hippocampus. This review will discuss in detail the complex process of adult hippocampal neurogenesis, including proliferation, differentiation, survival, and incorporation into neuronal networks. The regulation of this phenomenon by a number of factors is described, including neurotransmitter systems, growth factors, paracrine signaling molecules, neuropeptides, transcription factors, endogenous psychotropic systems, sex hormones, stress, and others. This review also addresses the functional significance of adult born hippocampal granule cells with regard to hippocampal circuitry dynamics and behavior. Furthermore, the relevance of perturbations in adult hippocampal neurogenesis to the pathophysiology of various disease states, including depression, schizophrenia, epilepsy, and diabetes are examined. Finally, this review discusses the potential of using hippocampal neurogenesis as a therapeutic target for these disorders. KeywordsNeurogenesis; hippocampus; depression; schizophrenia; epilepsy; diabetes; cognition; serotonin; stress; antidepressants; antipsychotics; BDNF Adult mammalian neurogenesis: historical perspective"In the adult centres, the nerve paths are something fixed, ended and immutable. Everything may die, nothing may be regenerated." -Santiago Ramon y Cajal, 1913 This statement highlights what was one of the central dogmas of neuroscience, that neurogenesis was restricted to prenatal and early postnatal development, and that the adult mammalian brain was unable to facilitate this process. However, in 1912, Ezra Allen provided the first hint of evidence that new neurons could be born in the adult mammalian brain, by showing mitotic figures in the walls of the lateral ventricles of albino rats up to 120 days of age (Allen, 1912). It was not until the 1960's where more evidence of the phenomenon was *Corresponding author: Dr. Irwin Lucki, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, Tel.: +1 215 573 3305, Fax: +1 215 573 2149, email: E-mail: lucki@pharm.med.upenn.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurosci Biobehav Rev. Author manuscript; available in PMC 2010 March 1. Published in final edited form as:Neurosci Biobehav Rev. 2009 March ; 33(3): 232-252. doi:10.1016/j.neubiorev.2008.007. NIH-PA...

Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

D-Serine modulates NMDA receptors and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of D-serine synthesis and release remains controversial, with some arguing that it is a “gliotransmitter” and others defining it as a “neuronal co-transmitter”. Results from several laboratories using different strategies now show that the D-serine’s biosynthetic enzyme, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain D-serine. Cell-selective suppression of serine racemase expression demonstrates that neuronal, rather than astrocytic D-serine, modulates synaptic plasticity. Here we propose an alternative conceptualization whereby astrocytes affect D-serine levels by synthesizing L-serine that shuttles to neurons to fuel the neuronal synthesis of D-serine.