Working Memory Deficits In Mice Research Articles

The GluN2C/D-specific positive allosteric modulator CIQ rescues delay-induced working memory deficits in mice

Working memory is of short duration and is, therefore, particularly sensitive to time delays. Moreover, NMDA receptors are significantly involved in working memory. In the present study, we tested whether a commonly used measure of working memory, spontaneous alternation in the Y-maze, is sensitive to time delays and, if so, whether impairments due to time-delay can be rescued by treatment with CIQ, a positive allosteric modulator of the GluN2C/D subunits of NMDA receptor. Our results indicate that the effects of time delay do depend on the performance of the individual mice under basal condition. Those mice that performed well under basal conditions showed impaired spontaneous alternations when tested with a 45-s delay. Treatment with CIQ resulted in an improvement of spontaneous alternations, regardless of delay, sex, or basal performance. On the one hand, our study shows that repeated measures of individual behavior can better control the effects of confounding factors such as time delays. On the other hand, our study also highlights the potential of GluN2C/D-specific positive allosteric modulators in the treatment of human disorders associated with working memory deficits, such as schizophrenia.

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.MethodsWe evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.Results Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03–0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.ConclusionsASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia.

N-methyl-D-aspartate (NMDA) receptor hypofunction leading to neural network dysfunction is thought to play an important role in the pathophysiology of cognitive impairment associated with schizophrenia (CIAS). Increasing extracellular concentrations of the NMDA receptor co-agonist glycine through inhibition of glycine transporter-1 (GlyT1) has the potential to treat CIAS by improving cortical network function through enhanced glutamatergic signaling. Indeed, the novel GlyT1 inhibitor iclepertin (BI 425809) improved cognition in a recent clinical study in patients with schizophrenia. The present study tested the ability of iclepertin to reverse deficits in auditory sensory processing and cortical network function induced by the uncompetetive NMDA receptor antagonist, MK-801, using electroencephalography (EEG) to measure auditory event-related potentials (AERPs) and 40 Hz auditory steady-state response (ASSR). In addition, improvements in memory performance with iclepertin were evaluated using the T-maze spontaneous alternation test in MK-801-treated mice and the social recognition test in naïve rats. Iclepertin reversed MK-801-induced deficits in the AERP readouts N1 amplitude and N1 gating, as well as reversing deficits in 40 Hz ASSR power and intertrial coherence. Additionally, iclepertin significantly attenuated an MK-801-induced increase in basal gamma power. Furthermore, iclepertin reversed MK-801-induced working memory deficits in mice and improved social recognition memory performance in rats. Overall, this study demonstrates that inhibition of GlyT1 is sufficient to attenuate MK-801-induced deficits in translatable EEG parameters relevant to schizophrenia. Moreover, iclepertin showed memory-enhancing effects in rodent cognition tasks, further demonstrating the potential for GlyT1 inhibition to treat CIAS. SIGNIFICANCE STATEMENT: Despite the significant patient burden caused by cognitive impairment associated with schizophrenia, there are currently no approved pharmacotherapies. In this preclinical study, the novel glycine transporter inhibitor iclepertin (BI 425809) reversed sensory processing deficits and neural network dysfunction evoked by inhibition of N-methyl-D-aspartate receptors and enhanced working memory performance and social recognition in rodents. These findings support previous clinical evidence for the procognitive effects of iclepertin.

The D2-family receptor agonist bromocriptine but, not nicotine, reverses NMDA receptor antagonist-induced working memory deficits in the radial arm maze in mice.

Hypofunction of the NMDA receptor (NMDAr) may underlie cognitive deficits associated with schizophrenia and other psychiatric conditions including working memory (WM) impairments. Given that these deficits link closely to functional outcome, treatments remediating such deficits require identification. NMDAr hypofunction can be modeled via treatment with the antagonist MK-801. Hence, the present study determined whether cholinergic or dopaminergic agonists attenuate MK-801-induced WM deficits in mice. WM was assessed in male C57BL/6 mice trained on an automated 12-arm radial arm maze (RAM) paradigm, wherein rewards were delivered after the first but, not after subsequent entries into WM arms (8/12) and never delivered for entries into reference memory (RM) arms (4/12). Mice were then treated with MK-801 (vehicle or 0.3mg/kg) and nicotine (vehicle, 0.03 or 0.30mg/kg) in a cross-over design. After a 2-week washout, mice were then retested with MK-801 and the dopamine D2-family receptor agonist bromocriptine (vehicle, 3 or 10mg/kg). In both experiments, MK-801 reduced WM span and increased RM and WM error rates. Nicotine did not attenuate these deficits. In contrast, a bromocriptine/MK-801 interaction was observed on WM error rate, where bromocriptine attenuated MK-801 induced deficits without affecting MK-801-induced RM errors. Additionally, bromocriptine produced the main effect of slowing latency to collect rewards. Hence, while NMDAr hypofunction-induced deficits in WM was unaffected by nicotine, it was remediated by treatment with the dopamine D2-family agonist bromocriptine. Future studies should determine whether selective activation of dopamine D2, D3, or D4 receptors remediate this NMDAr hypofunction-induced WM deficit.

Sustained corticosterone rise in the prefrontal cortex is a key factor for chronic stress-induced working memory deficits in mice

Exposure to prolonged, unpredictable stress leads to glucocorticoids-mediated long-lasting neuroendocrine abnormalities associated with emotional and cognitive impairments. Excessive levels of serum glucocorticoids (cortisol in humans, corticosterone in rodents) contribute notably to deficits in working memory (WM), a task which heavily relies on functional interactions between the medial prefrontal cortex (PFC) and the dorsal hippocampus (dHPC). However, it is unknown whether stress-induced increases in plasma corticosterone mirror corticosterone levels in specific brain regions critical for WM. After a 6 week-UCMS exposure, C57BL/6 J male mice exhibited increased anxiety- and depressive-like behaviors when measured one week later and displayed WM impairments timely associated with increased plasma corticosterone response. In chronically stressed mice, basal phosphorylated/activated CREB (pCREB) was markedly increased in the PFC and the CA1 area of the dHPC and WM testing did not elicit any further increase in pCREB in the two regions. Using microdialysis samples from freely-moving mice, we found that WM testing co-occurred with a rapid and sustained increase in corticosterone response in the PFC while there was a late, non-significant rise of corticosterone in the dHPC. The results also show that non-stressed mice injected with corticosterone (2 mg/kg i.p.) before WM testing displayed behavioral and molecular alterations similar to those observed in stressed animals while a pre-WM testing metyrapone injection (35 mg/kg i.p.), a corticosterone synthesis inhibitor, prevented the effects of UCMS exposure. Overall, the abnormal regional increase of corticosterone concentrations mainly in the PFC emerges as a key factor of enduring WM dysfunctions in UCMS-treated animals.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1β3γ2 and α5β3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

5-HT2A/C receptors mediate the antipsychotic-like effects of alstonine

The purpose of this study was to determine the effects of alstonine, an indole alkaloid with putative antipsychotic effects, on working memory by using the step-down inhibitory avoidance paradigm and MK801-induced working memory deficits in mice. Additionally, the role of serotonin 5-HT2A/C receptors in the effects of alstonine on mouse models associated with positive (MK801-induced hyperlocomotion), negative (MK801-induced social interaction deficit), and cognitive (MK801-induced working memory deficit) schizophrenia symptoms was examined. Treatment with alstonine was able to prevent MK801-induced working memory deficit, indicating its potential benefit for cognitive deficits now seen as a core symptom in the disease. Corroborating previously reported data, alstonine was also effective in counteracting MK801-induced hyperlocomotion and social interaction deficit. Ritanserin, a 5-HT2A/C receptor antagonist, prevented alstonine's effects on these three behavioral parameters. This study presents additional evidence that 5-HT2A/C receptors are central to the antipsychotic-like effects of alstonine, consistently seen in mouse models relevant to the three dimensions of schizophrenia symptoms.

AIT-082, a unique purine derivative, enhances nerve growth factor mediated neurite outgrowth from PC12 cells

AIT-082 is a novel, metabolically stable, derivative of the purine hypoxanthine. Addition of AIT-082 to cultured PC12 cells enhanced significantly nerve growth factor (NGF)-mediated neurite outgrowth from PC12 cells. These results suggest a cellular mechanism, the enhancement of NGF-action, that might account for the ability of AIT-082 to restore age-induced working memory deficits in mice.