RESUMEN

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Asunto(s)

Cicloserina , Haploinsuficiencia , Hipocampo , Potenciación a Largo Plazo , Trastornos de la Memoria , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Cicloserina/farmacología , Ratones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Noqueados , Masculino , Ratones Endogámicos C57BL , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Memoria/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/efectos de los fármacos

RESUMEN

Monocular deprivation (MD) causes an initial decrease in synaptic responses to the deprived eye in juvenile mouse primary visual cortex (V1) through Hebbian long-term depression (LTD). This is followed by a homeostatic increase, which has been attributed either to synaptic scaling or to a slide threshold for Hebbian long-term potentiation (LTP) rather than scaling. We therefore asked in mice of all sexes whether the homeostatic increase during MD requires GluN2B-containing NMDA receptor activity, which is required to slide the plasticity threshold but not for synaptic scaling. Selective GluN2B blockade from 2-6 d after monocular lid suture prevented the homeostatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude in monocular V1 of acute slices and prevented the increase in visually evoked responses in binocular V1 in vivo. The decrease in mEPSC amplitude and visually evoked responses during the first 2 d of MD also required GluN2B activity. Together, these results support the idea that GluN2B-containing NMDA receptors first play a role in LTD immediately following eye closure and then promote homeostasis during prolonged MD by sliding the plasticity threshold in favor of LTP.

Asunto(s)

Predominio Ocular , Potenciales Postsinápticos Excitadores , Ratones Endogámicos C57BL , Plasticidad Neuronal , Receptores de N-Metil-D-Aspartato , Animales , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Ratones , Masculino , Predominio Ocular/fisiología , Femenino , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Evocados Visuales/fisiología , Corteza Visual/fisiología , Corteza Visual/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Privación Sensorial/fisiología , Potenciación a Largo Plazo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Estimulación Luminosa/métodos

RESUMEN

Synaptic dysfunction is an early pathogenic event leading to cognitive decline in Huntington's disease (HD). We previously reported that the active ADAM10 level is increased in the HD cortex and striatum, causing excessive proteolysis of the synaptic cell adhesion protein N-Cadherin. Conversely, ADAM10 inhibition is neuroprotective and prevents cognitive decline in HD mice. Although the breakdown of cortico-striatal connection has been historically linked to cognitive deterioration in HD, dendritic spine loss and long-term potentiation (LTP) defects identified in the HD hippocampus are also thought to contribute to the cognitive symptoms of the disease. The aim of this study is to investigate the contribution of ADAM10 to spine pathology and LTP defects of the HD hippocampus. We provide evidence that active ADAM10 is increased in the hippocampus of two mouse models of HD, leading to extensive proteolysis of N-Cadherin, which has a widely recognized role in spine morphology and synaptic plasticity. Importantly, the conditional heterozygous deletion of ADAM10 in the forebrain of HD mice resulted in the recovery of spine loss and ultrastructural synaptic defects in CA1 pyramidal neurons. Meanwhile, normalization of the active ADAM10 level increased the pool of synaptic BDNF protein and activated ERK neuroprotective signaling in the HD hippocampus. We also show that the ADAM10 inhibitor GI254023X restored LTP defects and increased the density of mushroom spines enriched with GluA1-AMPA receptors in HD hippocampal neurons. Notably, we report that administration of the TrkB antagonist ANA12 to HD hippocampal neurons reduced the beneficial effect of GI254023X, indicating that the BDNF receptor TrkB contributes to mediate the neuroprotective activity exerted by ADAM10 inhibition in HD. Collectively, these findings indicate that ADAM10 inhibition coupled with TrkB signaling represents an efficacious strategy to prevent hippocampal synaptic plasticity defects and cognitive dysfunction in HD.

Asunto(s)

Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide , Hipocampo , Enfermedad de Huntington , Potenciación a Largo Plazo , Proteínas de la Membrana , Receptor trkB , Transducción de Señal , Animales , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Ratones , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Hipocampo/metabolismo , Hipocampo/patología , Receptor trkB/metabolismo , Receptor trkB/antagonistas & inhibidores , Potenciación a Largo Plazo/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Cadherinas/metabolismo , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Neuroprotección , Masculino , Ratones Endogámicos C57BL , Plasticidad Neuronal , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Ratones Noqueados

RESUMEN

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

Asunto(s)

Dieta Alta en Grasa , Hipocampo , Caracteres Sexuales , Animales , Masculino , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Receptores AMPA/metabolismo , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Grasas de la Dieta/farmacología

RESUMEN

Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aß accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aß-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aß. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aß from glutamatergic terminals. We believe that the selective pruning of Aß-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.

Asunto(s)

Aminopiridinas , Péptidos beta-Amiloides , Hipocampo , Potenciación a Largo Plazo , Microglía , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Péptidos beta-Amiloides/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aminopiridinas/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Pirroles/farmacología , Ratones , Fagocitosis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Ácido Glutámico/metabolismo

RESUMEN

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.

Asunto(s)

Núcleo Dorsal del Rafe , Fluoxetina , Ratones Endogámicos C57BL , Plasticidad Neuronal , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Inhibidores Selectivos de la Recaptación de Serotonina , Transmisión Sináptica , Animales , Fluoxetina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Femenino , Ratones , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/metabolismo , Embarazo , Masculino , Plasticidad Neuronal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Neuronas/efectos de los fármacos , Serotonina/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos

RESUMEN

The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU-POG; and PTU-RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted long­term potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using high­frequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10-90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10-90%), and amplitude of the fEPSP in the PTU­POG or PTU­RSG groups compared to the PTU group. TUNEL­positive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU-POG or PTU-RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU-POG or PTU-RSG groups, respectively, compared to the PTU group. This study's results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.

Asunto(s)

Apoptosis , Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Hipotiroidismo , Potenciación a Largo Plazo , PPAR gamma , Ratas Wistar , Rosiglitazona , Animales , Apoptosis/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Rosiglitazona/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , PPAR gamma/agonistas , PPAR gamma/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Tiazolidinedionas/farmacología , Pioglitazona/farmacología , Ratas , Propiltiouracilo/farmacología , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Óxido Nítrico/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo

RESUMEN

Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is an essential phenomenon in memory formation as well as maintenance along with many other cognitive functions, such as those needed for coping with external stimuli. Synaptic plasticity consists of gradual changes in the biochemistry and morphology of pre- and postsynaptic neurons, particularly in the hippocampus. Consuming marijuana as a primary source of exocannabinoids immediately impairs attention and working memory-related tasks. Evidence regarding the effects of cannabinoids on LTP and memory is contradictory. While cannabinoids can affect a variety of specific cannabinoid receptors (CBRs) and nonspecific receptors throughout the body and brain, they exert miscellaneous systemic and local cerebral effects. Given the increasing use of cannabis, mainly among the young population, plus its potential adverse long-term effects on learning and memory processes, it could be a future global health challenge. Indeed, the impact of cannabinoids on memory is multifactorial and depends on the dosage, timing, formula, and route of consumption, plus the background complex interaction of the endocannabinoids system with other cerebral networks. Herein, we review how exogenously administrated organic cannabinoids, CBRs agonists or antagonists, and endocannabinoids can affect LTP and synaptic plasticity through various receptors in interaction with other cerebral pathways and primary neurotransmitters.

Asunto(s)

Cannabinoides , Potenciación a Largo Plazo , Memoria , Plasticidad Neuronal , Cannabinoides/farmacología , Cannabinoides/metabolismo , Humanos , Plasticidad Neuronal/efectos de los fármacos , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Memoria/efectos de los fármacos , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Receptores de Cannabinoides/metabolismo , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos

RESUMEN

Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.

Asunto(s)

Artemisininas , N-Acetilglucosaminiltransferasas , Tauopatías , Proteínas tau , Animales , Humanos , Masculino , Ratones , Acetilglucosamina/metabolismo , Acetilglucosamina/farmacología , Artemisininas/farmacología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Simulación del Acoplamiento Molecular , N-Acetilglucosaminiltransferasas/metabolismo , Fármacos Neuroprotectores/farmacología , Fosforilación/efectos de los fármacos , Proteínas tau/metabolismo , Tauopatías/tratamiento farmacológico , Tauopatías/metabolismo

RESUMEN

The repeated use of small doses of psychedelics (also referred to as "microdosing") to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual's cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.

Asunto(s)

Nivel de Alerta , Atención , Electroencefalografía , Alucinógenos , Dietilamida del Ácido Lisérgico , Humanos , Masculino , Femenino , Adulto , Dietilamida del Ácido Lisérgico/farmacología , Dietilamida del Ácido Lisérgico/administración & dosificación , Adulto Joven , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Atención/efectos de los fármacos , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Memoria/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Método Doble Ciego , Cognición/efectos de los fármacos , Individualidad

RESUMEN

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 µg As L-1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 µg As L-1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

Asunto(s)

Arsénico , Hipocampo , Plasticidad Neuronal , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Arsénico/farmacología , Arsénico/toxicidad , Plasticidad Neuronal/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Hidrocarburos/farmacología , Calcio/metabolismo , Ratas , Masculino , Depresión Sináptica a Largo Plazo/efectos de los fármacos

RESUMEN

BACKGROUND: Study of synaptic integrity using conventional electrophysiology is a gold standard for quantitative assessment of neurodegeneration. Fluorescence assisted single-synapse long-term potentiation (FASS-LTP) provides a high throughput method to assess the synaptic integrity of neurotransmission within and between different brain regions as a measure of pharmacological efficacy in translational models. NEW METHOD: We adapted the existing method to our purpose by adding a step during the thawing of frozen samples, by an extra step of placing them on a rocker at room temperature for 30 minutes immediately following thawing with constant mixing on a shaker. This allowed for gradual, uniform thawing, effectively separating the synaptosomes. Our study demonstrates FASS-LTP on four brain regions at 6- and 12-month periods in the 3xTg-AD mouse model, treating sibling cohorts with VU0155069 (a small molecule inhibitor) or vehicle (0.9 % saline). RESULTS: Our findings demonstrate the robust ability of the FASS-LTP technique to characterize the functional synaptic integrity maintained by disease-treatment therapies in multiple brain regions longitudinally using frozen brain tissue. COMPARISON WITH EXISTING METHODS: By providing a detailed, user-friendly protocol for this well-known analysis and including a recovery step improved the ability to robustly replicate the FASS-LTP between different brain regions. This may be extrapolated to a translational use on human clinical samples to improve understanding of the therapeutic impact on synaptic performance related to glutamate neurotransmission. CONCLUSIONS: FASS-LTP method offers a robust analysis of synaptosomes isolated from frozen tissue samples, demonstrating greater reproducibility in rodent and human synapses in physiological and pathological states.

Asunto(s)

Encéfalo , Potenciación a Largo Plazo , Sinapsis , Animales , Encéfalo/fisiopatología , Encéfalo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Sinapsis/fisiología , Sinapsis/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Ratones , Ratones Transgénicos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Femenino

RESUMEN

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Asunto(s)

Adiponectina , Giro Dentado , Síndrome del Cromosoma X Frágil , Plasticidad Neuronal , Animales , Masculino , Ratones , Adiponectina/metabolismo , Adiponectina/farmacología , Giro Dentado/metabolismo , Giro Dentado/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Ratones Noqueados , Plasticidad Neuronal/efectos de los fármacos , Receptores AMPA/metabolismo

RESUMEN

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Asunto(s)

Péptidos beta-Amiloides , Encéfalo , Potenciación a Largo Plazo , Proteínas tau , Animales , Humanos , Masculino , Ratas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Ratas Transgénicas , Proteínas tau/metabolismo , Proteínas tau/farmacología

RESUMEN

The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vitro requires the blockade of the γ-aminobutyric acid A (GABAA) receptor. In these studies we examined the effectiveness of the specific GABAA receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two species commonly used for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 µM BMI. In contrast, a concentration of 10 µM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable LTP in the rodent DG in vitro and highlight the need to take consideration of the species being used when choosing concentrations of pharmacological agents to employ for electrophysiological use.NEW & NOTEWORTHY In this report we provide specific neurophysiological evidence for concentrations of GABAA antagonist required to study long-term potentiation in the medial perforant pathway of the dentate gyrus. Two commonly used species, Sprague-Dawley rats and C57Bl/6 mice, require different concentrations of bicuculline methiodide to induce optimal short-term and long-term potentiation.

Asunto(s)

Bicuculina , Giro Dentado , Antagonistas de Receptores de GABA-A , Potenciación a Largo Plazo , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Bicuculina/farmacología , Bicuculina/análogos & derivados , Antagonistas de Receptores de GABA-A/farmacología , Ratones , Ratas , Masculino , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiología , Especificidad de la Especie

RESUMEN

INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-ß oligomers (AßO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. HIGHLIGHTS: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Hipocampo , Ketamina , Ratones Transgénicos , Plasticidad Neuronal , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ketamina/análogos & derivados , Ketamina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Ratones , Potenciación a Largo Plazo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , ARN Mensajero/metabolismo , Memoria/efectos de los fármacos , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Ratones Endogámicos C57BL , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Humanos

RESUMEN

Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses can be altered. Although these two processes are mechanistically distinct, they converge on downstream regulation of AMPA receptor activity to modify glutamatergic neurotransmission. However, much remains to be explored regarding how these two prominent forms of plasticity interact. Ketamine, a rapidly acting antidepressant, increases glutamatergic transmission via pharmacologically-induced homeostatic plasticity. Here, we demonstrate that Hebbian plasticity mechanisms are still intact in synapses that have undergone homeostatic scaling by ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship in the context of stress induced by chronic exposure to corticosterone (CORT) to better model the circumstances under which ketamine may be used as an antidepressant. We found that CORT induced an anhedonia-like behavioral phenotype in mice but did not impair long-term potentiation (LTP) induction. Furthermore, corticosterone exposure does not impact the intersection of homeostatic and Hebbian plasticity mechanisms, as synapses from CORT-exposed mice also demonstrated intact ketamine-induced plasticity and LTP in succession. These results provide a mechanistic explanation for how ketamine used for the treatment of depression does not impair the integrity of learning and memory processes encoded by mechanisms such as LTP.

Asunto(s)

Corticosterona , Hipocampo , Ketamina , Potenciación a Largo Plazo , Ratones Endogámicos C57BL , Plasticidad Neuronal , Animales , Ketamina/farmacología , Corticosterona/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Masculino , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Antidepresivos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Estrés Psicológico/fisiopatología

RESUMEN

Short-chain fatty acids, such as butyric acid, derived from the intestinal fermentation of dietary fiber, have been proposed as a treatment for certain pathologies of the central nervous system. Our research group has shown that tributyrin (TB), a butyric acid prodrug, reverses deficits in spatial memory and modulates hippocampal synaptic plasticity. In the present work, diets enriched in either saturated (SOLF; Saturated OiL-enriched Food) or unsaturated (UOLF; Unsaturated OiL-enriched Food) fat were supplied during either 2 h or 8 weeks to 5-week-old male and female mice undergoing a treatment schedule with TB. After the dietary treatment, spatial learning and memory (SLM) was assessed in both the Y-maze and the eight-arm radial maze (RAM). Hippocampal expression of genes involved in glutamatergic transmission as well as synaptic plasticity (long-term potentiation -LTP- and long-term depression -LTD-) were also analyzed. Our results show that 2 h of SOLF intake impaired LTP as well as the performance in the Y-Maze in juvenile male mice whereas no effect was found in females. Moreover, TB reversed both effects in SLM and LTP in males. In the case of chronic intake, both SOLF and UOLF deteriorated SLM measured in the RAM in both sexes whereas TB only reversed LTP impairment induced by SOLF in male mice. These results suggest that TB may have a potentially beneficial influence on learning and memory processes, contingent upon the type of diet and the sex of the individuals.

Asunto(s)

Hipocampo , Memoria a Corto Plazo , Plasticidad Neuronal , Triglicéridos , Animales , Masculino , Femenino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Triglicéridos/metabolismo , Memoria a Corto Plazo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Caracteres Sexuales , Grasas de la Dieta/efectos adversos , Ácidos Grasos/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos

RESUMEN

Traumatic brain injury (TBI) leads to changes in the neural circuitry of the hippocampus that result in chronic learning and memory deficits. However, effective therapeutic strategies to ameliorate these chronic learning and memory impairments after TBI are limited. Two pharmacological targets for enhancing cognition are nicotinic acetylcholine receptors (nAChRs) and GABAA receptors (GABAARs), both of which regulate hippocampal network activity to form declarative memories. A promising compound, 522-054, both allosterically enhances α7 nAChRs and inhibits α5 subunit-containing GABAARs. Administration of 522-054 enhances long-term potentiation (LTP) and cognitive functioning in non-injured animals. In this study, we assessed the effects of 522-054 on hippocampal synaptic plasticity and learning and memory deficits in the chronic post-TBI recovery period. Adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 12 wk after injury, we assessed basal synaptic transmission and LTP at the Schaffer collateral-CA1 synapse of the hippocampus. Bath application of 522-054 to hippocampal slices reduced deficits in basal synaptic transmission and recovered TBI-induced impairments in LTP. Moreover, treatment of animals with 522-054 at 12 wk post-TBI improved cue and contextual fear memory and water maze acquisition and retention without a measurable effect on cortical or hippocampal atrophy. These results suggest that dual allosteric modulation of α7 nAChR and α5 GABAAR signaling may be a potential therapy for treating cognitive deficits during chronic recovery from TBI.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Ratas Sprague-Dawley , Receptores de GABA-A , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Masculino , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Ratas , Receptores de GABA-A/metabolismo , Regulación Alostérica/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología

RESUMEN

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (µg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.

Asunto(s)

Hipocampo , Lipopolisacáridos , Potenciación a Largo Plazo , Neuroesteroides , Animales , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Lipopolisacáridos/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Neuroesteroides/metabolismo , Receptores Toll-Like/metabolismo , Aprendizaje/efectos de los fármacos , Ratones , Plasticidad Neuronal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Hidroxicolesteroles/farmacología , Hidroxicolesteroles/metabolismo , Pregnanolona/farmacología , Pregnanolona/metabolismo