GABA-cAMP Response Element-Binding Protein Signaling Regulates Maturation and Survival of Newly Generated Neurons in the Adult Hippocampus

Jagasia, Ravi; Steib, Kathrin; Englberger, Elisabeth; Herold, Sabine; Faus-Keßler, Theresa; Saxe, Michael; Gage, Fred H.; Song, Hongjun; Lie, Dieter Chichung

doi:10.1523/jneurosci.1054-09.2009

Cited by 311 publications

(354 citation statements)

References 65 publications

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“…APα-induced proliferation was mediated via GABA A receptor-activated voltagegated L-type Ca 2+ channels (1) leading to a rapid rise in intracellular calcium in neural progenitors (38). In neural progenitor cells, the high intracellular chloride content leads to an efflux of chloride through the GABA A channels upon opening, which leads to depolarization of the membrane and influx of Ca 2+ through voltage dependent L-type Ca 2+ channels and activation of the CREB transcription factor (1,38,39). Through this pathway, APα stimulation of GABA-mediated excitation and CREB signaling can activate a key pathway in adult hippocampal neurogenesis, to promote the proliferation, survival, and differentiation of neural progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

240

266

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Our previous analyses showed that allopregnanolone (APα) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APα-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

240

266

View full text Add to dashboard Cite

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“…Because activated/phosphorylated cAMP-response element binding protein (pCREB) is known to be associated with Bdnf and Ntf3 and is important for learning and memory (24)(25)(26)(27), the level of pCREB was also determined. A significant reduction in pCREB was observed in irradiated WT mice (80% reduction, t = 2.62, P < 0.05), implying a diminished level of pCREB-mediated neuronal function in this cohort.…”

Section: Ec-sod and Irradiation Affect Expression Of Neurotrophic Facmentioning

confidence: 99%

Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation

Zou¹,

Corniola²,

Leu

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampalrelated functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that highlevel EC-SOD may provide protection against irradiation-related defects in hippocampal functions.

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“…The chronological localization pattern of CREB-immunoreactivity in rats is similar to that of VIAAT in the present mouse gland. Since there have been studies suggesting that CREB signalling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation (Fukuchi et al, 2014;Jagasia et al, 2009), the similarity in the chronological localization between CREB and VIAAT/GABA may lead us to consider the possibility that the signalling cascade of the two molecules plays roles in the postnatal development of the salivary glandular cells. In support of this possibility in the peripheral organ, there has recently been accumulating evidence on the role of tonic GABAergic currents during early brain development (Kilb et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Localization of Vesicular Inhibitory Amino Acid Transporter (VIAAT) in the Submandibular Salivary Gland Throughout the Postnatal Development of Mice

et al. 2015

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SUMMARY:According to recent studies, it is highly possible that the occurrence of vesicular inhibitory amino acid transporter (VIAAT) is a good marker of GABA-signaling not only in the brain, but also in extra-brain tissue cells containing GABA and GAD. In view of this, the present study was attempted to localize VIAAT-immunoreactivity in the submandibular gland of mice. In the present study, the submandibular glands of male mice at various postnatal developmental stages were examined for detailed localization of VIAAT-immunoreactivity in immunohistochemistry at light microscopic level. The immunoreactivity for VIAAT was localized in epithelial cells of proximal and distal excretory ducts with the striated portion more intensely immunopositive at young postnatal stages. No significant immunoreactivity was seen in the acinar cells throughout the postnatal development. In addition, the immunoreactivity for VIAAT was detected in the salivary parasympathetic ganglionic neurons, but not in any nerve fibers surrounding the glandular cells. Furthermore, VIAAT-immunoreactivity was found in smooth muscle cells forming the outermost layer of intralobular arterioles. From the present findings, it is possible that GABA plays roles as paracrine and autocrine regulators in the saliva secretion as well as the gland development.

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GABA-cAMP Response Element-Binding Protein Signaling Regulates Maturation and Survival of Newly Generated Neurons in the Adult Hippocampus

Cited by 311 publications

References 65 publications

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation

Localization of Vesicular Inhibitory Amino Acid Transporter (VIAAT) in the Submandibular Salivary Gland Throughout the Postnatal Development of Mice

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