Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

Ongoing neurogenesis in the adult hippocampal dentate gyrus (DG) generates a substantial population of young neurons. This phenomenon is present in all species examined thus far, including humans. Although the regulation of adult neurogenesis by various physiologically relevant factors such as learning and stress has been documented, the functional contributions of the newly born neurons to hippocampal functions are not known. We investigated possible contributions of the newly born granule neurons to synaptic plasticity in the hippocampal DG. In the standard hippocampal slice preparation perfused with artificial cerebrospinal fluid (ACSF), a small (10%) long-term potentiation (LTP) of the evoked field potentials is seen after tetanic stimulation of the afferent medial perforant pathway (MPP). The induction of this ACSF-LTP is resistant to a N-methyl-d-aspartate (NMDA) receptor blocker,d,l-2-amino-5-phosphonovaleric acid (APV), but is completely prevented by ifenprodil, a blocker of NR2B subtype of NMDA receptors. In contrast, slices perfused with picrotoxin (PICRO), a GABA-receptor blocker, revealed a larger (40–50%), APV-sensitive but ifenprodil-insensitive LTP. The ACSF-LTP required lower frequency of stimulation and fewer stimuli for its induction than the PICRO-LTP. All these characteristics of ACSF-LTP are in agreement with the properties of the putative individual new granule neurons examined previously with the use of the whole cell recording technique in a similar preparation. A causal relationship between neurogenesis and ACSF-LTP was confirmed in experiments using low dose of gamma radiation applied to the brain 3 wk prior to the electrophysiological experiments. In these experiments, the new cell proliferation was drastically reduced and ACSF-LTP was selectively blocked. We conclude that the young, adult-generated granule neurons play a significant role in synaptic plasticity in the DG. Since DG is the major source of the afferent inputs into the hippocampus, the production and the plasticity of new neurons may have an important role in the hippocampal functions such as learning and memory.

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Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

PLoS ONE ◽

10.1371/journal.pone.0007901 ◽

2009 ◽

Vol 4 (11) ◽

pp. e7901 ◽

Cited By ~ 83

Author(s):

Elodie Bruel-Jungerman ◽

Alexandra Veyrac ◽

Franck Dufour ◽

Jennifer Horwood ◽

Serge Laroche ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Akt Signaling

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Chronic Intermittent Hypoxia (CIH) Impairs Neurogenesis and Alters Paired Pulse Synaptic Plasticity In the Dentate Gyrus of Hippocampus

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.681.4 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Maggie Khuu ◽

Rebecca Hodge ◽

Jan‐Marino Ramirez ◽

Alfredo Garcia

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Paired Pulse

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Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG

BMC Biology ◽

10.1186/s12915-020-00877-2 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Sofía Espinoza ◽

Sebastián B. Arredondo ◽

Francisca Barake ◽

Francisco Carvajal ◽

Fernanda G. Guerrero ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Lupus Erythematosus ◽

Tyrosine Phosphatase ◽

Unmet Need ◽

Long Term Potentiation ◽

Structural Features ◽

Synaptic Activity ◽

E3 Ligases

Abstract Background Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Results Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. Conclusions NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.

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Immunocytochemical Identification of Mammalian Differentiating Neurons in the Process of Adult Neurogenesis in the Hippocampal Dentate Gyrus

Neuromethods - Immunocytochemistry and Related Techniques ◽

10.1007/978-1-4939-2313-7_6 ◽

2015 ◽

pp. 109-122 ◽

Cited By ~ 1

Author(s):

Oliver von Bohlen und Halbach

Keyword(s):

Dentate Gyrus ◽

Adult Neurogenesis ◽

Hippocampal Dentate Gyrus

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Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus

The Journal of Comparative Neurology ◽

10.1002/cne.1040 ◽

2001 ◽

Vol 435 (4) ◽

pp. 406-417 ◽

Cited By ~ 1071

Author(s):

Heather A. Cameron ◽

Ronald D.G. Mckay

Keyword(s):

Dentate Gyrus ◽

Adult Neurogenesis ◽

Granule Cells ◽

Large Pool

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Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

Neural Plasticity ◽

10.1155/2014/917981 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Jeremy D. Coplan ◽

Shariful Syed ◽

Tarique D. Perera ◽

Sasha L. Fulton ◽

Mary Ann Banerji ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Body Weight ◽

Dentate Gyrus ◽

Body Mass ◽

Adult Neurogenesis ◽

Plasma Lipids ◽

High Plasma ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

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Levetiracetam Reduced the Basal Excitability of the Dentate Gyrus without Restoring Impaired Synaptic Plasticity in Rats with Temporal Lobe Epilepsy

Brain Sciences ◽

10.3390/brainsci10090634 ◽

2020 ◽

Vol 10 (9) ◽

pp. 634

Author(s):

Guillermo González-H ◽

Itzel Jatziri Contreras-García ◽

Karla Sánchez-Huerta ◽

Claudio M. T. Queiroz ◽

Luis Ricardo Gallardo Gudiño ◽

...

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Focal Epilepsy ◽

Chronic Phase ◽

Long Term Potentiation ◽

Excitatory Postsynaptic Potential ◽

Output Curve

Temporal lobe epilepsy (TLE), the most common type of focal epilepsy, affects learning and memory; these effects are thought to emerge from changes in synaptic plasticity. Levetiracetam (LEV) is a widely used antiepileptic drug that is also associated with the reversal of cognitive dysfunction. The long-lasting effect of LEV treatment and its participation in synaptic plasticity have not been explored in early chronic epilepsy. Therefore, through the measurement of evoked field potentials, this study aimed to comprehensively identify the alterations in the excitability and the short-term (depression/facilitation) and long-term synaptic plasticity (long-term potentiation, LTP) of the dentate gyrus of the hippocampus in a lithium–pilocarpine rat model of TLE, as well as their possible restoration by LEV (1 week; 300 mg/kg/day). TLE increased the population spike (PS) amplitude (input/output curve); interestingly, LEV treatment partially reduced this hyperexcitability. Furthermore, TLE augmented synaptic depression, suppressed paired-pulse facilitation, and reduced PS-LTP; however, LEV did not alleviate such alterations. Conversely, the excitatory postsynaptic potential (EPSP)-LTP of TLE rats was comparable to that of control rats and was decreased by LEV. LEV caused a long-lasting attenuation of basal hyperexcitability but did not restore impaired synaptic plasticity in the early chronic phase of TLE.

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