Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

Download Full-text

Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2015.04.007 ◽

2015 ◽

Vol 36 (8) ◽

pp. 2391-2405 ◽

Cited By ~ 39

Author(s):

Cindy K. Barha ◽

Stephanie E. Lieblich ◽

Carmen Chow ◽

Liisa A.M. Galea

Keyword(s):

Spatial Memory ◽

Middle Age ◽

Hippocampal Neurogenesis ◽

Ovarian Hormone ◽

Hormone Status

Download Full-text

Early-Life Stress Does Not Aggravate Spatial Memory or the Process of Hippocampal Neurogenesis in Adult and Middle-Aged APP/PS1 Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2018.00061 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Lianne Hoeijmakers ◽

Anna Amelianchik ◽

Fleur Verhaag ◽

Janssen Kotah ◽

Paul J. Lucassen ◽

...

Keyword(s):

Spatial Memory ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Hippocampal Neurogenesis ◽

Middle Aged

Download Full-text

Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice

Behavioral and Brain Functions ◽

10.1186/s12993-015-0075-7 ◽

2015 ◽

Vol 11 (1) ◽

Cited By ~ 25

Author(s):

Yuan Yang ◽

Meikui Zhang ◽

Xiaoni Kang ◽

Chen Jiang ◽

Huan Zhang ◽

...

Keyword(s):

Spatial Memory ◽

Microglial Activation ◽

Hippocampal Neurogenesis ◽

Memory Ability

Download Full-text

The Effect of Acori Graminei Rhizoma and Extract Fractions on Spatial Memory and Hippocampal Neurogenesis in Amyloid Beta 1-42 Injected Mice

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527314666150225124348 ◽

2015 ◽

Vol 14 (3) ◽

pp. 411-420 ◽

Cited By ~ 15

Author(s):

Yuxin Ma ◽

Sumin Tian ◽

Lingzhi Sun ◽

Shizhang Yao ◽

Zihao Liang ◽

...

Keyword(s):

Spatial Memory ◽

Amyloid Beta ◽

Hippocampal Neurogenesis

Download Full-text

Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815197116 ◽

2019 ◽

Vol 116 (22) ◽

pp. 10988-10993 ◽

Cited By ~ 15

Author(s):

Jang Soo Yook ◽

Randeep Rakwal ◽

Junko Shibato ◽

Kanako Takahashi ◽

Hikaru Koizumi ◽

...

Keyword(s):

Spatial Memory ◽

Direct Action ◽

Memory Function ◽

Neuroblastoma Cell ◽

Hippocampal Neurogenesis ◽

Human Neuroblastoma Cell ◽

Bioinformatics Analyses ◽

Human Neuroblastoma ◽

Beneficial Effects ◽

Protein Levels

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, ABHD3, but also that the up-regulation of LEP gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (ob/ob), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.

Download Full-text

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0569-x ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Jaewoo Shin ◽

Chanho Kong ◽

Jihyeon Lee ◽

Bo Young Choi ◽

Jiyeon Sim ◽

...

Keyword(s):

Spatial Memory ◽

Water Maze ◽

Focused Ultrasound ◽

Amyloid Β ◽

Acetylcholinesterase Activity ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Cholinergic Degeneration ◽

Barrier Opening ◽

Blood Brain Barrier Opening

Abstract Background The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer’s disease (AD). The neuropathologies of AD include the presence of amyloid-β deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-β proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. Methods Adult male Sprague-Dawley rats (n = 48; 200–250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2′-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey’s multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant. Results Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication. Conclusions FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.

Download Full-text