Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods

The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.

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Constitutive AP2gamma deficiency reduces postnatal hippocampal neurogenesis and induces behavioral deficits in juvenile mice that persist during adulthood

10.1101/2021.06.07.447328 ◽

2021 ◽

Author(s):

Eduardo Loureiro-Campos ◽

Nuno Dinis Alves ◽

António Mateus-Pinheiro ◽

Patrícia Patrício ◽

Carina Soares-Cunha ◽

...

Keyword(s):

Dorsal Hippocampus ◽

Hippocampal Neurogenesis ◽

Heterozygous Deletion ◽

Cumulative Impact ◽

Postnatal Brain ◽

Early Postnatal Development ◽

Cognitive Behaviors ◽

Glutamatergic Neurons ◽

Important Regulator ◽

And Behavior

The transcription factor activating protein two gamma (AP2gamma) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive AP2gamma heterozygous deletion in mice from early postnatal development until adulthood. Constitutive AP2gamma heterozygous deletion in mice caused a reduction of hippocampal transient amplifying progenitors (TAPs) in the postnatal brain, inducing significant impairments on hippocampal-dependent emotional- and cognitive-behavioral tasks including anxiety-like behavior and cognitive deficits, typically associated with an intact neurogenic activity. Moreover, AP2gamma deficiency impairs dorsal hippocampus-to-prefrontal cortex functional connectivity. We observed a progressive and cumulative impact of constitutive AP2gamma deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with impairments on emotional and cognitive behaviors from juvenile to adult periods. Collectively, the results herein presented demonstrate the importance of AP2gamma in the generation of glutamatergic neurons in the postnatal brain and its impact on behavioral performance.

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GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02059-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Dan Song ◽

Yaohua Chen ◽

Cheng Chen ◽

Lili Chen ◽

Oumei Cheng

Keyword(s):

Cognitive Function ◽

Cerebral Ischemia ◽

Learning And Memory ◽

Spatial Learning ◽

Hippocampal Neurogenesis ◽

Morris Water Maze Test ◽

Spatial Learning And Memory ◽

In Vitro Experiments ◽

Adult Mice

Abstract Purpose and background Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI. Methods Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot. Results CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs. Conclusion Inhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

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Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006138117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25818-25829

Author(s):

Xinxing Wang ◽

Hanxiao Liu ◽

Johannes Morstein ◽

Alexander J. E. Novak ◽

Dirk Trauner ◽

...

Keyword(s):

Dentate Gyrus ◽

Energy Homeostasis ◽

Inhibitory Neuron ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Neuron Activity ◽

Adult Mice ◽

Sphingosine 1 Phosphate ◽

Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

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Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

Molecular Neurobiology ◽

10.1007/s12035-019-1496-3 ◽

2019 ◽

Vol 56 (9) ◽

pp. 6218-6238 ◽

Cited By ~ 2

Author(s):

Bangrong Cai ◽

Kyung-Joo Seong ◽

Sun-Woong Bae ◽

Min Suk Kook ◽

Changju Chun ◽

...

Keyword(s):

Microglial Activation ◽

Mapk Signaling ◽

Hippocampal Neurogenesis ◽

Water Soluble ◽

Adult Mice

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Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors

Endocrine Related Cancer ◽

10.1677/erc-08-0127 ◽

2009 ◽

Vol 16 (1) ◽

pp. 267-279 ◽

Cited By ~ 24

Author(s):

Yu-Cheng Wang ◽

Emerick Gallego-Arteche ◽

Gioia Iezza ◽

Xiaochen Yuan ◽

Mary R Matli ◽

...

Keyword(s):

Transcription Factor ◽

Endocrine Cells ◽

Homeodomain Transcription Factor ◽

Normal Tissues ◽

Adult Mice ◽

The Central Nervous System ◽

Normal Intestine ◽

Marker Expression ◽

Glucagon Like Peptide 1 ◽

Novel Target

The homeodomain transcription factor NKX2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that NKX2.2 is important for NE differentiation in normal and neoplastic gut. NKX2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of NKX2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (−/−) mice was examined by IF and real-time (RT)-PCR. NKX2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. NKX2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting NKX2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (−/−) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. NKX2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude NKX2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.

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Neuroligin-2 and the tightrope of excitation/inhibition balance in the prefrontal cortex

Journal of Neurophysiology ◽

10.1152/jn.00703.2015 ◽

2016 ◽

Vol 115 (1) ◽

pp. 5-7 ◽

Cited By ~ 5

Author(s):

Alice M. S. Durieux ◽

Jamie Horder ◽

Marija M. Petrinovic

Keyword(s):

Prefrontal Cortex ◽

Neuropsychiatric Disorders ◽

Conditional Knockout ◽

Adhesion Protein ◽

Inhibition Ratio ◽

Adult Mice ◽

Behavioral Impairments

Excitation/inhibition imbalance is implicated in symptoms of neuropsychiatric disorders. We discuss a study by Liang et al. ( Mol Psychiatry 20: 850–859, 2015) demonstrating that the conditional knockout of neuroligin-2, a postsynaptic adhesion protein, in the prefrontal cortex of adult mice results in alterations in inhibitory synaptic properties. However, behavioral impairments emerged prior to the development of detectable changes in excitation/inhibition ratio. This suggests there may be network-specific excitation/inhibition ratios, some of which are more vulnerable to disruption than others.

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Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1703920114 ◽

2017 ◽

Vol 114 (17) ◽

pp. E3536-E3545 ◽

Cited By ~ 97

Author(s):

Qianfa Long ◽

Dinesh Upadhya ◽

Bharathi Hattiangady ◽

Dong-Ki Kim ◽

Su Yeon An ◽

...

Keyword(s):

Status Epilepticus ◽

Memory Function ◽

Hippocampal Neurogenesis ◽

Medical Emergency ◽

Memory Impairments ◽

Functional Deficits ◽

Persistent Inflammation ◽

Antiepileptic Drug Treatment ◽

Antiinflammatory Effects

Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrow-derived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.

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