Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces

Garzón, Javier; Rodríguez-Muñoz, María; Cortés-Montero, Elsa; Sánchez‐Blázquez, Pilar

doi:10.1038/srep43468

Cited by 17 publications

(43 citation statements)

References 82 publications

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“…32 In brief, sperm lysates were prepared using a buffer containing 50 mM Tris, pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, and 0.2% NP-40 along with protease inhibitor cocktail. Caudal sperm were incubated in non-capacitating and capacitating medium with/without FK506 (20 nM).…”

Section: In Vitro Calcineurin Activity Assaymentioning

confidence: 99%

“…From a duplicate pool of untreated caput and caudal epididymal sperm cells, cellular lysates were prepared using the Calcineurin Cellular Activity Assay Kit, Enzo Life Sciences (BML-AK816). 32 In brief, sperm lysates were prepared using a buffer containing 50 mM Tris, pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, and 0.2% NP-40 along with protease inhibitor cocktail. Background phosphates were removed from the extracts using a kit-provided desalting column.…”

Section: In Vitro Calcineurin Activity Assaymentioning

confidence: 99%

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Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs

et al. 2019

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Glycogen synthase kinase 3 (GSK3) was identified as an enzyme regulating sperm protein phosphatase. The GSK3α paralog, but not GSK3β, is essential for sperm function. Sperm lacking GSK3α display altered motility and are unable to undergo hyperactivation, which is essential for fertilization. Male mice lacking sperm‐specific calcineurin (PP2B), a calcium regulated phosphatase, in testis and sperm, are also infertile. Loss of PP2B results in impaired epididymal sperm maturation and motility. The phenotypes of GSK3α and PP2B knockout mice are similar, prompting us to examine the interrelationship between these two enzymes in sperm. High calcium levels must exist to permit catalytically active calcineurin to function during epididymal sperm maturation. Total and free calcium levels are high in immotile compared to motile epididymal sperm. Inhibition of calcineurin by FK506 results in an increase in the net phosphorylation and a consequent decrease in catalytic activity of sperm GSK3. The inhibitor FK506 and an isoform‐selective inhibitor of GSK3α, BRD0705, also inhibited fertilization of eggs in vitro. Interrelated functions of GSK3α and sperm PP2B are essential during epididymal sperm maturation and during fertilization. Our results should enable the development of male contraceptives targeting one or both enzymes.

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Section: In Vitro Calcineurin Activity Assaymentioning

confidence: 99%

Section: In Vitro Calcineurin Activity Assaymentioning

confidence: 99%

Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs

et al. 2019

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“…Furthermore, another study using HINT1 KO mice suggested HINT1 KO mice exhibited behavioral and molecular alterations paralleling those described in BP patients. Thus, HINT1 KO mice could be used as an appropriate model for studying BP and may help identify novel targets and drugs to treat this mental disorder [ 52 ].…”

Section: Hint1 In Neuropsychiatric Disordersmentioning

confidence: 99%

HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator

Liu

Wang

et al. 2017

Neural Plasticity

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Although many studies have investigated the functions of histidine triad nucleotide-binding protein 1 (HINT1), its roles in neurobiological processes remain to be fully elucidated. As a member of the histidine triad (HIT) enzyme superfamily, HINT1 is distributed in almost every organ and has both enzymatic and nonenzymatic activity. Accumulating clinical and preclinical evidence suggests that HINT1 may play an important role as a neuroplastic mediator in neuropsychiatric diseases, such as schizophrenia, inherited peripheral neuropathies, mood disorders, and drug addiction. Though our knowledge of HINT1 is limited, it is believed that further research on the neuropathological functions of HINT1 would eventually benefit patients with neuropsychiatric and even psychosomatic diseases.

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“…Interestingly, mood stabilizers such as lithium salts and valproate diminished these activities displayed by BStac mice without altering those of BScr mice ( Juetten and Einat, 2012 ). Thus, the activity of BStac mice is highly sensitive to low doses of amphetamine, and its enhancement is prevented by mood stabilizers ( Flaisher-Grinberg and Einat, 2010 ) and GSK3β inhibitors ( Kalinichev and Dawson, 2011 ; Garzón-Niño et al, 2017 ). On the other hand, mice with a genetic deletion of histidine triad nucleotide-binding protein 1 (HINT1) also display manic-like behaviors.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, mice with a genetic deletion of histidine triad nucleotide-binding protein 1 (HINT1) also display manic-like behaviors. HINT1 -/- mice rapidly switch into depressive-like behaviors in response to stressful situations ( Garzón-Niño et al, 2017 ). In contrast, the elevated manic activity of BStac mice predominates and prevents stress from triggering the mechanisms necessary to reduce mobility in the FST.…”

Section: Introductionmentioning

confidence: 99%

Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice

Sánchez‐Blázquez

Cortés-Montero

Rodríguez-Muñoz

et al. 2018

International Journal of Neuropsychopharmacology

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BackgroundSeveral currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease.MethodsIn this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the “manic” Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors.ResultsThe activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3β inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the “bipolar” HINT1−/− mice during pro-depressive episodes.Conclusionsσ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.

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Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces

Cited by 17 publications

References 82 publications

Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs

Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs

HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator

Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice

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