Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

Phenyl-2-aminoethyl selenide ameliorates hippocampal long-term potentiation and cognitive deficits following doxorubicin treatment.

Chemotherapy-induced memory loss ("chemobrain") can occur following treatment with the widely used chemotherapeutic agent doxorubicin (DOX). However, the mechanisms through which DOX induces cognitive dysfunction are not clear, and there are no commercially available therapies for its treatment or prevention. Therefore, the aim of this study was to determine the therapeutic potential of phenyl-2-aminoethyl selenide (PAESe), an antioxidant drug previously demonstrated to reduce cardiotoxicity associated with DOX treatment, against DOX-induced chemobrain. Four groups of male athymic NCr nude (nu/nu) mice received five weekly tail-vein injections of saline (Control group), 5 mg/kg of DOX (DOX group), 10 mg/kg PAESe (PAESe group), or 5 mg/kg DOX and 10 mg/kg PAESe (DOX+PAESe group). Spatial memory was evaluated using Y-maze and novel object location tasks, while synaptic plasticity was assessed through the measurement of field excitatory postsynaptic potentials from the Schaffer collateral circuit. Western blot analyses were performed to assess hippocampal protein and phosphorylation levels. In this model, DOX impaired synaptic plasticity and memory, and increased phosphorylation of protein kinase B (Akt) and extracellular-regulated kinase (ERK). Co-administration of PAESe reduced Akt and ERK phosphorylation and ameliorated the synaptic and memory deficits associated with DOX treatment.

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits.

Doxorubicin (Dox) is a chemotherapeutic agent used widely to treat a variety of malignant cancers. However, Dox chemotherapy is associated with several adverse effects, including "chemobrain," the observation that cancer patients exhibit through learning and memory difficulties extending even beyond treatment. This study investigated the effect of Dox treatment on learning and memory as well as hippocampal synaptic plasticity. Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and a significant reduction in hippocampal long-term potentiation. The deficit in synaptic plasticity was mirrored by deficits in the functionality of synaptic `α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, including reduced probability of opening, decreased dwell open time, and increased closed times. Furthermore, a reduction in the AMPAR subunit GluA1 level, its downstream signaling molecule Ca2+/calmodulin-dependent protein kinase (CaMKII), and brain-derived neurotrophic factor (BDNF) were observed. This was also accompanied by an increase in extracellular signal regulated kinase (ERK) and protein kinase B (AKT) activation. Together these data suggest that Dox-induced cognitive impairments are at least partially due to alterations in the expression and functionality of the glutamatergic AMPAR system.

Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring.

Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress.

Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer's model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge.

Peripheral infections can potently exacerbate neuropathological conditions, though the underlying mechanisms are poorly understood. We have previously demonstrated that intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces a robust generation of CXCL10 chemokine in the hippocampus. The hippocampus also features hyperexcitability of neuronal circuits following PIC challenge. The present study was undertaken to determine the role of CXCL10 in mediating the development of hyperexcitability in response to PIC challenge. Briefly, young female C57BL/6 mice were i.p. injected with PIC, and after 24 h, the brains were analyzed by confocal microscopy. CXCL10 staining of neuronal perikarya and a less intense staining of the neuropil was observed in the hippocampus and cortex. CXCL10 staining was also evident in a subpopulation of astrocytes, whereas microglia were CXCL10 negative. CXCR3, the cognate receptor of CXCL10 was present exclusively on neurons, indicating that the CXCL10/CXCR3 axis operates through an autocrine/paracrine neuronal signaling. Blocking cerebral CXCR3 through intracerebroventricular injection of a specific inhibitor, AMG487, abrogated PIC challenge-induced increase in basal synaptic transmission and long-term potentiation (LTP), as well as the reduction of paired-pulse facilitation (PPF), in the hippocampus. The PIC-mediated abolishment of hippocampal long-term depression (LTD) was also restored after administration of AMG487. Moreover, CXCR3 inhibition attenuated seizure hypersensitivity induced by PIC challenge. The efficacy of AMG487 strongly strengthens the notion that CXCL10/CXCR3 axis mediates the induction of cerebral hyperexcitability by PIC challenge.

Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

AIMS: This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents. MAIN METHODS: Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated. KEY FINDINGS: Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Complex-I and IV activities, increased Caspase-1 and 3 activities, had no effect on cholinergic neurotransmission, increased expression of PSD-95, decreased LTP and decreased performance on spatial memory tasks. However, nicotine exposure, in addition to alcohol exposure, was found to mitigate the negative effects of alcohol alone on ROS generation and spatial memory task performances. Furthermore, we also studied the role of ILK in prenatal alcohol and nicotine exposure. SIGNIFICANCE: Prenatal Smoking and/or drinking is a major health concern around the world. Thus, our current study may lead to better insights into the molecular mechanisms of fetal alcohol and nicotine exposure on the developing offspring.

Adiponectin Knockout Mice Display Cognitive and Synaptic Deficits.

Adiponectin is an adipokine that has recently been under investigation for potential neuroprotective effects in various brain disorders including Alzheimer's disease, stroke, and depression. Adiponectin receptors (AdipoR1 and AdipoR2) are found throughout various brain regions, including the hippocampus. However, the role of these receptors in synaptic and cognitive function is not clear. Therefore, the goal of the current study was to evaluate synaptic and cognitive function in the absence of adiponectin. The current study utilized 12-month-old adiponectin knockout (APN-KO) mice and age-matched controls to study cognitive and hippocampal synaptic alterations. We determined that AdipoR1 and AdipoR2 are present in the synaptosome, with AdipoR2 displaying increased presynaptic vs. postsynaptic localization, whereas AdipoR1 was enriched in both the presynaptic and postsynaptic fractions. APN-KO mice displayed cognitive deficits in the novel object recognition (NOR) and Y-maze tests. This was mirrored by deficits in long-term potentiation (LTP) of the hippocampal Schaefer collateral pathway in APN-KO mice. APN-KO mice also displayed a reduction in basal synaptic transmission and an increase in presynaptic release probability. Deficits in LTP were rescued through hippocampal slice incubation with the adiponectin receptor agonist, AdipoRon, indicating that acute alterations in adiponectin receptor signaling influence synaptic function. Along with the deficits in LTP, altered levels of key presynaptic and postsynaptic proteins involved in glutamatergic neurotransmission were observed in APN-KO mice. Taken together, these results indicate that adiponectin is an important regulator of cognition and synaptic function in the hippocampus. Future studies should examine the role of specific adiponectin receptors in synaptic processes.

PPAR-δ Activation Ameliorates Diabetes-Induced Cognitive Dysfunction by Modulating Integrin-linked Kinase and AMPA Receptor Function.

An estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer's disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the db/db mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in db/db mice. PPAR-δ-mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory.

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.

Prenatal cannabinoid exposure and altered neurotransmission.

Marijuana is one of the most commonly used illicit drugs worldwide. In addition, use of synthetic cannabinoids is increasing, especially among adolescents and young adults. Although human studies have shown that the use of marijuana during pregnancy leads to adverse behavioral effects, such as deficiencies in attention and executive function in affected offspring, the rate of marijuana use among pregnant women is steadily increasing. Various aspects of human behavior including emotion, learning, and memory are dependent on complex interactions between multiple neurotransmitter systems that are especially vulnerable to alterations during the developmental period. Thus, exploration of neurotransmitter changes in response to prenatal cannabinoid exposure is crucial to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral deficits manifest following the abuse of marijuana or other synthetic cannabinoids during pregnancy. Current literature confirms that vast alterations to neurotransmitter systems are present following prenatal cannabinoid exposure, and many of these alterations within the brain are region specific, time-dependent, and sexually dimorphic. In this review, we aim to provide a summary of observed changes to various neurotransmitter systems following cannabinoid exposure during pregnancy and to draw possible correlations to reported behavioral alterations in affected offspring.

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

Role of Adiponectin in Central Nervous System Disorders.

Adiponectin, the most abundant plasma adipokine, plays an important role in the regulation of glucose and lipid metabolism. Adiponectin also possesses insulin-sensitizing, anti-inflammatory, angiogenic, and vasodilatory properties which may influence central nervous system (CNS) disorders. Although initially not thought to cross the blood-brain barrier, adiponectin enters the brain through peripheral circulation. In the brain, adiponectin signaling through its receptors, AdipoR1 and AdipoR2, directly influences important brain functions such as energy homeostasis, hippocampal neurogenesis, and synaptic plasticity. Overall, based on its central and peripheral actions, recent evidence indicates that adiponectin has neuroprotective, antiatherogenic, and antidepressant effects. However, these findings are not without controversy as human observational studies report differing correlations between plasma adiponectin levels and incidence of CNS disorders. Despite these controversies, adiponectin is gaining attention as a potential therapeutic target for diverse CNS disorders, such as stroke, Alzheimer's disease, anxiety, and depression. Evidence regarding the emerging role for adiponectin in these disorders is discussed in the current review.

Assessment of the cerebellar neurotoxic effects of nicotine in prenatal alcohol exposure in rats.

The adverse effects of prenatal nicotine and alcohol exposure on human reproductive outcomes are a major scientific and public health concern. In the United States, substantial percentage of women (20-25%) of childbearing age currently smoke cigarettes and consume alcohol, and only a small percentage of these individuals quit after learning of their pregnancy. However, there are very few scientific reports on the effect of nicotine in prenatal alcohol exposure on the cerebellum of the offspring. Therefore, this study was conducted to investigate the cerebellar neurotoxic effects of nicotine in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). In this study, we evaluated the behavioral changes, biochemical markers of oxidative stress and apoptosis, mitochondrial functions and the molecular mechanisms associated with nicotine in prenatal alcohol exposure on the cerebellum. Prenatal nicotine and alcohol exposure induced oxidative stress, did not affect the mitochondrial functions, increased the monoamine oxidase activity, increased caspase expression and decreased ILK, PSD-95 and GLUR1 expression without affecting the GSK-3ß. Thus, our current study of prenatal alcohol and nicotine exposure on cerebellar neurotoxicity may lead to new scientific perceptions and novel and suitable therapeutic actions in the future.

Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation.

Retrieval of a memory appears to render it unstable until the memory is once again re-stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.

Impaired insulin signaling and mechanisms of memory loss.

Insulin is secreted from the ß-cells of the pancreas and helps maintain glucose homeostasis. Although secreted peripherally, insulin also plays a profound role in cognitive function. Increasing evidence suggests that insulin signaling in the brain is necessary to maintain health of neuronal cells, promote learning and memory, decrease oxidative stress, and ultimately increase neuronal survival. This chapter summarizes the different facets of insulin signaling necessary for learning and memory and additionally explores the association between cognitive impairment and central insulin resistance. The role of impaired insulin signaling in the advancement of cognitive dysfunction is relevant to the current debate of whether the shared pathophysiological mechanisms between diabetes and cognitive impairment implicate a direct relationship. Here, we summarize a vast amount of literature that suggests a strong association between impaired brain insulin signaling and cognitive impairment.