Increased Prefrontal Cortex Neurogranin Enhances Plasticity and Extinction Learning

Zhong, Ling; Brown, Joshua C.; Kramer, Audra A.; Kaleka, Kanwardeep S.; Petersen, Amber; Krueger, Jamie N.; Florence, Matthew A.; Muelbl, Matthew J.; Battle, Michelle; Murphy, Geoffrey G.; Olsen, Christopher M.; Gerges, Nashaat Z.

doi:10.1523/jneurosci.0274-15.2015

Cited by 26 publications

(26 citation statements)

References 29 publications

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“…Nrgn had recently been suggested as cerebrospinal fluid biomarker for AD (36,37). Forced expression of Nrgn enhances local synaptic plasticity in mice (38). Nrgn associates with the postsynaptic density (39) and with neuronal exosomes (14).…”

Section: Discussionmentioning

confidence: 99%

An N-terminal motif unique to primate tau enables differential protein–protein interactions

Stefanoska

Volkerling

Bertz

et al. 2018

Journal of Biological Chemistry

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Compared with other mammalian species, humans are particularly susceptible to taumediated neurodegenerative disorders. Differential interactions of the tau protein with other proteins are critical for mediating tau's physiological functions as well as tauassociated pathological processes. Primate tau harbors an 11-amino-acid-long motif in its Nterminal region (residues 18-28), which is not present in non-primate species and whose function is unknown. Here, we used deletion mutagenesis to remove this sequence region from the longest human tau isoform, followed by glutathione-S transferase (GST) pulldown assays paired with isobaric tags for relative and absolute quantitation (iTRAQ) multiplex labeling, a quantitative method to measure protein abundance by mass spectrometry.

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Section: Discussionmentioning

confidence: 99%

An N-terminal motif unique to primate tau enables differential protein–protein interactions

Stefanoska

Volkerling

Bertz

et al. 2018

Journal of Biological Chemistry

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“…Levels of Ng in the hippocampus are positively correlated with hippocampus-dependent learning performance (Huang et al, 2004). Loss of Ng in mice causes an impairment of spatial learning, in addition to altering synaptic plasticity in the hippocampus (Pak et al, 2000), whereas increasing Ng levels in the prefrontal cortex facilitates memory extinction and synaptic plasticity at prefrontal glutamatergic synapses (Zhong et al, 2015). Together, these findings suggest an important role of Ng in regulating synaptic plasticity in the central nervous system.…”

Section: Introductionmentioning

confidence: 98%

Experience-Dependent Equilibration of AMPAR-Mediated Synaptic Transmission during the Critical Period

Han

Cooke

2017

Cell Reports

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Experience-dependent synapse refinement is essential for functional optimization of neural circuits. However, how sensory experience sculpts excitatory synaptic transmission is poorly understood. Here, we show that despite substantial remodeling of synaptic connectivity, AMPAR-mediated synaptic transmission remains at equilibrium during the critical period in the mouse primary visual cortex. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity. With normal visual experience, loss of Ng decreased AMPAR-positive synapse numbers, prevented AMPAR-silent synapse maturation, and increased spine elimination. Importantly, visual deprivation halted synapse loss caused by loss of Ng, revealing that Ng coordinates experience-dependent AMPAR-silent synapse conversion to AMPAR-active synapses and synapse elimination. Loss of Ng also led to sensitized long-term synaptic depression (LTD) and impaired visually guided behavior. Our synaptic interrogation reveals that experience-dependent coordination of AMPAR-silent synapse conversion and synapse elimination hinges upon Ng-dependent mechanisms for constructive synaptic refinement during the critical period.

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“…In this context, there is a growing interest in developing novel biomarkers that would monitor other aspects of AD pathology such as for example synaptic dysfunction and neuroinflammation and two such biomarkers, neurogranin and YKL‐40, have recently emerged. Neurogranin is calmodulin‐binding postsynaptic protein regulating synaptic plasticity and learning . Several studies demonstrated that neurogranin levels are reduced in the brain but increased in CSF of AD patients .…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid neurogranin and YKL ‐40 as biomarkers of Alzheimer's disease

Bateman

Hertze

Zetterberg

et al. 2015

Ann Clin Transl Neurol

152

125

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ObjectiveWidespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non‐AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL‐40, a marker of neuroinflammation.Methods CSF neurogranin and YKL‐40 were measured in a cohort of 338 individuals including cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI who later developed AD (MCI‐AD), AD dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD). The diagnostic accuracy of neurogranin and YKL‐40 were compared with the core AD biomarkers, β‐amyloid (Aβ42 and Aβ40) and tau.ResultsNeurogranin levels were increased in AD and decreased in non‐AD dementia compared with healthy controls. As a result, AD patients showed considerably higher CSF levels of neurogranin than DLB/PDD, VaD and FTD patients. CSF YKL‐40 levels were increased in AD compared with DLB/PDD but not with VaD or FTD. Neither CSF neurogranin nor YKL‐40 levels differed significantly between sMCI patients and MCI‐AD patients. Both biomarkers correlated positively with CSF Aβ40 and tau. CSF neurogranin and YKL‐40 could separate AD dementia from non‐AD dementias (neurogranin, area under the curve [AUC] = 0.761; YKL‐40, AUC = 0.604; Aβ42/neurogranin, AUC = 0.849; Aβ42/YKL‐40, AUC = 0.785), but the diagnostic accuracy was not better compared to CSF Aβ and tau (Aβ42, AUC = 0.755; tau AUC = 0.858; Aβ42/tau, AUC = 0.895; Aβ42/Aβ40, AUC = 0.881). Similar results were obtained when separating sMCI from MCI‐AD cases.Interpretation CSF neurogranin and YKL‐40 do not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to the core CSF AD biomarkers. Nevertheless, the CSF level of neurogranin is selectively increased in AD dementia, whereas YKL‐40 is increased in both AD and FTD suggesting that synaptic degeneration and glial activation may be important in these neurodegenerative conditions.

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Increased Prefrontal Cortex Neurogranin Enhances Plasticity and Extinction Learning

Cited by 26 publications

References 29 publications

An N-terminal motif unique to primate tau enables differential protein–protein interactions

An N-terminal motif unique to primate tau enables differential protein–protein interactions

Experience-Dependent Equilibration of AMPAR-Mediated Synaptic Transmission during the Critical Period

Cerebrospinal fluid neurogranin and YKL ‐40 as biomarkers of Alzheimer's disease

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