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1.
Cereb Cortex ; 30(4): 2144-2156, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32142100

ABSTRACT

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker ß-amyloid (Aß). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aß accumulation. Here, we tested whether the relationship between cortical Aß accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aß correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aß relationship followed closely the Aß accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aß accumulation may involve Homer1 activity in the cortical regions, where harbor Aß deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Cerebral Cortex/metabolism , Cognitive Dysfunction/metabolism , Homer Scaffolding Proteins/biosynthesis , Sleep Wake Disorders/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Cerebral Cortex/diagnostic imaging , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/genetics , Cross-Sectional Studies , Female , Gene Expression , Homer Scaffolding Proteins/genetics , Humans , Longitudinal Studies , Magnetic Resonance Imaging/methods , Male , Middle Aged , Positron-Emission Tomography/methods , Self Report , Sleep Wake Disorders/diagnostic imaging , Sleep Wake Disorders/genetics
2.
Article in English | MEDLINE | ID: mdl-31404590

ABSTRACT

Type-5 metabotropic glutamate receptors (mGlu5) have been implicated in the mechanism of resilience to stress. They form part of the postsynaptic density (PSD), a thickening of the glutamatergic synapse that acts as a multimodal hub for multiple cellular signaling. Perinatal stress in rats triggers alterations that make adult offspring less resilient to stress. In the present study, we examined the expression of gene encoding the mGlu5 (Grm5), as well as those encoding the short and long isoforms of Homer proteins in different brain regions of the offspring of dams exposed to repeated episodes of restraint stress during pregnancy ("perinatally stressed" or PRS offspring). To this end, we investigated unconditioned behavioral response using the light/dark box test, as well as the expression of PSD genes (Homer1a, Homer1b, and Grm5), in the medial prefrontal cortex, cortex, caudate-putamen, amygdala, and dorsal hippocampus. PRS rats spent significantly less time in the light area than the control group. In the amygdala, Homer1a mRNA levels were significantly increased in PRS rats, whereas Homer1b and Grm5 mRNA levels were reduced. In contrast, the transcript encoding for Homer1a was significantly reduced in the medial prefrontal cortex, caudate-putamen, and dorsal hippocampus of PRS rats. We also evaluated the relative ratio between Homer1a and Homer1b/Grm5 expression, finding a significant shift toward the expression of Homer1a in the amygdala and toward Homer1b/Grm5 in the other brain regions. These topographic patterns of Homer1a, Homer1b, and mGlu5 gene expression were significantly correlated with risk-taking behavior measured in the light/dark box test. Remarkably, in the amygdala and in other brain regions, Homer1b and Grm5 expression showed positive correlation with time spent in the light box, whereas Homer1a in the amygdala showed a negative correlation with risk-taking behavior, in contrast with all other brain regions analyzed, wherein these correlations were positive. These results suggest that perinatal stress programs the developmental expression of PSD molecules involved in mGlu5 signaling in discrete brain regions, with a predominant role for the amygdala.


Subject(s)
Brain/metabolism , Homer Scaffolding Proteins/biosynthesis , Post-Synaptic Density/metabolism , Receptor, Metabotropic Glutamate 5/biosynthesis , Stress, Psychological/metabolism , Stress, Psychological/psychology , Animals , Female , Gene Expression , Homer Scaffolding Proteins/genetics , Male , Post-Synaptic Density/genetics , Pregnancy , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5/genetics , Restraint, Physical
3.
Neurochem Int ; 129: 104515, 2019 10.
Article in English | MEDLINE | ID: mdl-31369778

ABSTRACT

Lysophosphatidic acid (LPA) is a glycerophospholipid that can be detected in serum, saliva and cerebrospinal fluid. However, the effect of LPA on neuronal death and survival has not been fully determined. In the present study, we investigated the potential neurotoxic effect of LPA in primary cultured cortical neurons. Treatment with LPA (0.5, 1 and 5 µM) markedly decreased neuronal viability, increased lactate dehydrogenase (LDH) release and promoted apoptosis in cortical neurons. The results of western blot showed that LPA increased the expression of endoplasmic reticulum (ER) stress associated factors, and the protein misfolding inhibitor 4-phenylbutyric acid (4-PBA) attenuated LPA-induced toxicity. In addition, treatment with LPA did not alter the expression and distribution of Homer1 in cortical neurons. The protein levels of metabotropic glutamate receptor 1 (mGluR1), but not metabotropic glutamate receptor 5 (mGluR5), were significantly increased by LPA at 12 and 24 h after treatment. Knockdown of Homer1 using specific siRNA partially prevented the LPA-induced neurotoxicity and ER stress. Furthermore, the results of Ca2+ imaging showed that treatment with LPA induced intracellular Ca2+ release, which could be partially prevented by 4-PBA and downregulation of Homer1. The LPA-induced intracellular Ca2+ release was associated with ER Ca2+ release through the Homer1-mGluR1 pathway. In summary, our results showed that LPA treatment induced ER stress and apoptosis in cortical neurons, and its neurotoxicity was partially mediated by Ca2+ release from the ER via the Homer1/mGluR1 pathway.


Subject(s)
Calcium Signaling/drug effects , Endoplasmic Reticulum Stress/drug effects , Homer Scaffolding Proteins/physiology , Lysophospholipids/toxicity , Nerve Tissue Proteins/physiology , Neurons/drug effects , Receptors, Metabotropic Glutamate/physiology , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Down-Regulation , Female , Homer Scaffolding Proteins/antagonists & inhibitors , Homer Scaffolding Proteins/biosynthesis , Homer Scaffolding Proteins/genetics , Nerve Tissue Proteins/antagonists & inhibitors , Neurons/metabolism , Phenylbutyrates/pharmacology , Primary Cell Culture , RNA Interference , RNA, Small Interfering/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5/biosynthesis , Receptor, Metabotropic Glutamate 5/genetics , Receptors, Metabotropic Glutamate/biosynthesis , Receptors, Metabotropic Glutamate/genetics
4.
Psychopharmacology (Berl) ; 235(5): 1347-1359, 2018 05.
Article in English | MEDLINE | ID: mdl-29234834

ABSTRACT

Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is available over prolonged periods of time. Here, we investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and gene expression in the dorsal medial prefrontal cortex (dmPFC) in adult male rats. Rats were allowed to self-administer intravenous cocaine (0.25 mg/infusion) under either limited cocaine-(1 h/day), prolonged cocaine-(6 h/day), or limited cocaine-(1 h/day) plus yoked cocaine-access (5 h/day); a control group received access to saline (1 h/day). One day after the final self-administration session, the rats were euthanized and the dmPFC was removed for quantification of mRNA expression of critical glutamatergic signaling genes, Homer2, Grin1, and Dlg4, as these genes and brain region have been previously implicated in addiction, learning, and memory. All groups with cocaine-access showed escalated cocaine intake during the first 10 min of each daily session, and within the first 1 h of cocaine administration. Additionally, the limited-access + yoked group exhibited more non-reinforced lever responses during self-administration sessions than the other groups tested. Lastly, Homer2, Grin1, and Dlg4 mRNA were impacted by both duration and mode of cocaine exposure. Only prolonged-access rats exhibited increases in mRNA expression for Homer2, Grin1, and Dlg4 mRNA. Taken together, these findings indicate that both contingent and non-contingent "excessive" cocaine exposure supports escalation behavior, but the behavioral contingency of cocaine-access has distinct effects on the patterning of operant responsiveness and changes in mRNA expression.


Subject(s)
Cocaine-Related Disorders/metabolism , Cocaine/administration & dosage , Disks Large Homolog 4 Protein/biosynthesis , Homer Scaffolding Proteins/biosynthesis , Receptors, N-Methyl-D-Aspartate/biosynthesis , Animals , Behavior, Addictive/genetics , Behavior, Addictive/metabolism , Cocaine/adverse effects , Cocaine-Related Disorders/genetics , Disks Large Homolog 4 Protein/genetics , Gene Expression , Homer Scaffolding Proteins/genetics , Male , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/genetics , Self Administration
5.
J Psychopharmacol ; 31(8): 1078-1087, 2017 08.
Article in English | MEDLINE | ID: mdl-28720013

ABSTRACT

Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with "cognitive enhancer" use by individuals treated with selective serotonin reuptake inhibitors. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of selective serotonin reuptake inhibitors potentiates these methylphenidate-induced molecular effects, thus producing a more "cocaine-like" profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers ( Zif268, c- Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c- Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate + selective serotonin reuptake inhibitor-induced "cocaine-like" effects.


Subject(s)
Corpus Striatum/drug effects , Gene Expression Regulation/drug effects , Genes, Immediate-Early/drug effects , Methylphenidate/pharmacology , Receptor, Serotonin, 5-HT1B/physiology , Animals , Corpus Striatum/metabolism , Dose-Response Relationship, Drug , Drug Synergism , Early Growth Response Protein 1/biosynthesis , Fluoxetine/pharmacology , Homer Scaffolding Proteins/biosynthesis , Locomotion/drug effects , Male , Proto-Oncogene Proteins c-fos/biosynthesis , Pyridines/pharmacology , Rats , Serotonin 5-HT1 Receptor Agonists/pharmacology
6.
Int J Mol Sci ; 17(12)2016 Dec 17.
Article in English | MEDLINE | ID: mdl-27999308

ABSTRACT

BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/therapy , Homer Scaffolding Proteins/biosynthesis , Lithium/therapeutic use , Superoxide Dismutase/genetics , Valproic Acid/therapeutic use , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Apoptosis/genetics , Cell Line , Genetic Predisposition to Disease , Homer Scaffolding Proteins/antagonists & inhibitors , Homer Scaffolding Proteins/genetics , Humans , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , RNA, Small Interfering/genetics
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