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Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer's Disease.
Farr SA, Roesler E, Niehoff ML, Roby DA, McKee A, Morley JE
(2019) J Alzheimers Dis 68: 1699-1710
MeSH Terms: Alzheimer Disease, Animals, Disease Models, Animal, Maze Learning, Memory, Metformin, Mice, Neuroprotective Agents, Treatment Outcome
Show Abstract · Added April 30, 2019
Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer's disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCɛ), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.
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9 MeSH Terms
Inhibition of Glycogen Synthase Kinase 3β as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury.
Farr SA, Niehoff ML, Kumar VB, Roby DA, Morley JE
(2019) J Neurotrauma 36: 1869-1875
MeSH Terms: Animals, Brain Injuries, Traumatic, Cognitive Dysfunction, Glycogen Synthase Kinase 3 beta, Maze Learning, Mice, Oligonucleotides, Antisense
Show Abstract · Added March 12, 2019
Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3β (GSK-3β) in its phosphorylated form (p-GSK-3β) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3β (AO) gene. Using a model of closed-head concussive TBI, we subjected mice to TBI and injected AO or a random antisense (AO) 15 min post-injury. One week post-injury, mice were tested in object recognition with 24 h delay. At 4 weeks post- injury, mice were tested with a T-maze foot shock avoidance memory test and a second object recognition test with 24 h delay using different objects. Mice that received AO show improved memory in both object recognition and T-maze compared with AO- treated mice that were subjected to TBI. Next, we verified that AO blocked the surge in phosphorylated GSK-3β post-TBI. Mice were subjected to TBI and injected with antisense 15 min post-TBI with AO or AO. Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3β, p-tyr216GSK-3β, and phospho-tau (p-tau) showed that mice that received a TBI+AO had significantly higher p-ser9GSK-3β, p-tyr216GSK-3β, and p-tau levels than the mice that received TBI+AO and the Sham+AO mice. The current finding suggests that inhibiting GSK-3β increase after TBI with an antisense directed at GSK-3β prevents learning and memory impairments.
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7 MeSH Terms
HCN channels in the hippocampus regulate active coping behavior.
Fisher DW, Han Y, Lyman KA, Heuermann RJ, Bean LA, Ybarra N, Foote KM, Dong H, Nicholson DA, Chetkovich DM
(2018) J Neurochem 146: 753-766
MeSH Terms: Adaptation, Psychological, Animals, Avoidance Learning, Depression, Disease Models, Animal, Exploratory Behavior, Hippocampus, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Maze Learning, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Peroxins, Pyramidal Cells, Swimming
Show Abstract · Added April 2, 2019
Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (I ) in the CA1 area increases with chronic mild stress. Reduction of I in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of I is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in I in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style.
© 2018 International Society for Neurochemistry.
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18 MeSH Terms
Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Bedse G, Bluett RJ, Patrick TA, Romness NK, Gaulden AD, Kingsley PJ, Plath N, Marnett LJ, Patel S
(2018) Transl Psychiatry 8: 92
MeSH Terms: Amidohydrolases, Animals, Anti-Anxiety Agents, Anxiety Disorders, Behavior, Animal, Benzodioxoles, Body Temperature, Brain, Carbamates, Endocannabinoids, Female, Locomotion, Male, Maze Learning, Mice, Inbred C57BL, Mice, Inbred ICR, Monoacylglycerol Lipases, Piperazines, Piperidines, Pyridines, Stress, Psychological
Show Abstract · Added April 12, 2019
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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MeSH Terms
OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood G, Tanaka KF, Moore H, Ahmari SE, Veenstra-VanderWeele J
(2017) Proc Natl Acad Sci U S A 114: 5719-5724
MeSH Terms: Amphetamines, Animals, Basal Ganglia, Cell Line, Central Nervous System Stimulants, Dopamine, Excitatory Amino Acid Transporter 3, Glutamic Acid, Grooming, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Obsessive-Compulsive Disorder, Receptors, Dopamine D1, Reflex, Startle
Show Abstract · Added March 18, 2020
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in () locomotor activity, () stereotypy, and () immediate early gene induction in the dorsal striatum following amphetamine administration. Further, -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D receptor binding in the dorsal striatum of -STOP mice. -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
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MeSH Terms
Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease.
McClure R, Ong H, Janve V, Barton S, Zhu M, Li B, Dawes M, Jerome WG, Anderson A, Massion P, Gore JC, Pham W
(2017) J Alzheimers Dis 55: 797-811
MeSH Terms: Administration, Inhalation, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Anti-Inflammatory Agents, Non-Steroidal, Cognition Disorders, Curcumin, Dendritic Spines, Disease Models, Animal, Hippocampus, Humans, Maze Learning, Memory, Short-Term, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mutation, Neurons, Presenilin-1
Show Abstract · Added April 10, 2017
We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.
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22 MeSH Terms
Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.
Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ
(2015) J Neurosci 35: 15326-38
MeSH Terms: Age Factors, Animals, Brain, Castration, Dizocilpine Maleate, Epilepsy, Reflex, Exploratory Behavior, Female, Gene Expression Regulation, Glutamate Decarboxylase, Lyases, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Selenium, Selenoprotein P, Sex Factors, Transcription Factors
Show Abstract · Added March 29, 2016
UNLABELLED - Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.
SIGNIFICANCE STATEMENT - Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.
Copyright © 2015 the authors 0270-6474/15/3515326-13$15.00/0.
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23 MeSH Terms
IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z
(2015) Aging Cell 14: 1034-44
MeSH Terms: Aging, Animals, Brain, Cerebrovascular Circulation, Cognition Disorders, Disease Models, Animal, Insulin-Like Growth Factor I, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Microvessels, Neurovascular Coupling, Nitric Oxide, Spatial Memory
Show Abstract · Added March 10, 2016
Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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16 MeSH Terms
Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism.
Burket JA, Benson AD, Green TL, Rook JM, Lindsley CW, Conn PJ, Deutsch SI
(2015) Prog Neuropsychopharmacol Biol Psychiatry 61: 10-7
MeSH Terms: Analysis of Variance, Animals, Benzamides, Dose-Response Relationship, Drug, Glycine Plasma Membrane Transport Proteins, Male, Maze Learning, Memory, Short-Term, Mice, Mice, Inbred BALB C, Mice, Inbred ICR, Piperidines, Social Behavior, Spatial Learning, Stereotyped Behavior
Show Abstract · Added February 18, 2016
The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.
Copyright © 2015 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles.
Rook JM, Tantawy MN, Ansari MS, Felts AS, Stauffer SR, Emmitte KA, Kessler RM, Niswender CM, Daniels JS, Jones CK, Lindsley CW, Conn PJ
(2015) Neuropsychopharmacology 40: 755-65
MeSH Terms: Allosteric Regulation, Amphetamine, Animals, Benzamides, Calcium, Cerebellum, Corpus Striatum, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Locomotion, Male, Maze Learning, Niacinamide, Piperidines, Positron-Emission Tomography, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Thiazoles
Show Abstract · Added February 19, 2015
Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.
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21 MeSH Terms