Enhanced Object Recognition Memory Research Articles

Role of medial prefrontal cortex voltage-dependent potassium 4.3 channels in nicotine-induced enhancement of object recognition memory in male mice

Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N’-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory.

Electrophysiological and Pharmacological Research on Neural Activity in the Neocortex and Hippocampus During Sleep

Sleep is fundamental for living animals. Although they are not conscious during sleep, their brains are continuously working. This neural activity during sleep can be reflected by neural oscillations closely related to cognitive function. While the relationship between neural activity in sleep and cognition has been extensively investigated, it is not fully understood how neural activity in sleep and relevant memory are modulated by specific receptors. In particular, I focused on melatonin receptors and their agonist, ramelteon. While the effects of ramelteon on sleep have been widely documented, it is still poorly understood how ramelteon affects learning and memory as well as neural activity in sleep. To address this question, I first recorded neural oscillations in the neocortex of rats treated with ramelteon and found that ramelteon promoted non-rapid eye movement (NREM) sleep and increased fast gamma power in the primary motor cortex during NREM sleep. I then evaluated the behavioral performance of ramelteon-treated mice using the novel object recognition task and the spontaneous alternation task, demonstrating that ramelteon enhanced object recognition memory and spatial working memory. These results shed light on new aspects of the functions of melatonin receptors.

Diet enriched with high-phenolic cocoa potentiates hippocampal brain-derived neurotrophic factor expression and neurogenesis in healthy adult micewith subtle effects on memory.

Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks. In a first experiment, behavioral tests assessing exploratory behavior, emotional responses and hippocampal-dependent memory were conducted four weeks into the diet, followed by animal sacrifice a week later. Adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex were evaluated using immunohistochemistry and western blot. In a different experiment, hippocampal synaptic response, long-term potentiation and presynaptic-dependent short-term plasticity were studied by electrophysiology. Cocoa-enriched diets had minimal effects on exploratory activity and anxiety-like behavior, except for reduced locomotion in the LPC group. Only the HPC diet enhanced object recognition memory, while place recognition memory and spatial navigation remained unaffected. The HPC diet also increased adult hippocampal neurogenesis, boosting the proliferation, survival and number of young adult-born neurons. However, both cocoa-enriched diets increased immobility in the forced swimming test and hippocampal BDNF expression. Hippocampal electrophysiology revealed no alterations in neuroplasticity among diets. The results were mostly unaffected by sex. Overall, the HPC diet demonstrated greater potential regarding cognitive and neuroplastic benefits, suggesting a key role of cocoa flavanols in dietary interventions aimed at enhancing brain health.

Effects of long‐term oral treatment with a novel estrogen receptor beta agonist on memory, vasomotor, and anxiety outcomes in an EFAD mouse model of Alzheimer’s disease

AbstractBackgroundThe prevalence and severity of Alzheimer’s disease (AD) are increased by female sex, apolipoprotein E (APOE) genotype, and age, such that postmenopausal female carriers of the Apoe4 allele are at greater risk of developing AD than age‐matched males. Although estrogen therapy shows promise in preventing and reducing menopause‐ and AD‐related symptoms, activation of estrogen receptor alpha (ERa) is associated with increased risk for health concerns, such as breast cancer. Therefore, treatments more selective for estrogen receptor beta (ERb) may provide estrogen‐related health benefits without the risks of activating ERa. Long‐term or acute treatment of wild‐type mice with the novel ERb agonist, EGX358, improves memory and reduces drug‐induced vasomotor alterations. However, efficacy of this compound in an AD model is unknown.MethodFemale APOE‐TR+/+/5xFAD+/− (EFAD) mice expressed five familial AD and were homozygous for human APOE3 (E3FAD) or heterozygous for APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and then treated orally with vehicle (1% DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Mice were weighed weekly and tested for spatial and object memory in the object placement (OP) and object recognition (OR) tasks, respectively. Anxiety‐like behaviors were also tested in the open field and elevated plus maze, and vasomotor symptoms were assessed via tail temperature following injection of the tachykinin receptor 3 agonist, senktide.ResultEGX358 significantly enhanced OR memory in both E3FAD and E3/4FAD mice. However, treatment did not affect OP memory or anxiety in the open field or elevated plus maze. Interestingly, there were significant genotype differences in open field, vasomotor response, and body weight such that E3/4FADs spent more time in the center of open field, had a greater increase in tail temperature following senktide injection, and gained more weight compared to E3FADs.ConclusionOur findings indicate a potential for ERβ‐specific estrogen treatment to improve memory for the identity of objects. Unexpected genotype differences indicate the need to further study how APOE genotype affects anxiety and metabolic outcomes in AD.

Effects of melatonin on phosphorylation of memory-related proteins in the hippocampus and the perirhinal cortex in male mice.

We recently demonstrated that a single post-training administration of either melatonin, an MT1/MT2 melatonin receptor agonist ramelteon, or a brain melatonin metabolite N1-acetyl-5-methoxyquinuramine (AMK) enhanced object recognition memory. The present study aims to investigate the effects of melatonin, ramelteon, and AMK on relative phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor-mediated and nonreceptor-mediated memory-enhancing effects of melatonin. We first confirmed that post-training administration of either melatonin, ramelteon, or AMK at 1 mg/kg promoted long-term memory formation, using the novel object recognition task. Next, the effects of the same doses of these drugs on relative phosphorylation levels of the extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinases (CaMKs) in the hippocampus and the perirhinal cortex (PRC) were examined by western blot analysis. In the hippocampus, treatment with ramelteon or AMK significantly increased and decreased phosphorylation levels of ERK and cAMP-response element binding protein (CREB) and those of CaMKIIα and β, respectively. In the PRC, phosphorylation levels of ERK and those of CaMKIIβ were significantly increased by both ramelteon and AMK and by ramelteon, respectively. Neither ramelteon nor AMK altered the phosphorylation levels of CaMKIV in either hippocampus or PRC. These results suggest that melatonin may be involved in promoting the formation of long-term object recognition memory in a similar, if not identical, manner by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways.

Enhancement of memory consolidation by an avoidance conditioned stimulus: Modulation by the D3 receptor

Conditioned stimuli (CS) paired with foot-shock can enhance memory consolidation. Because the dopamine D3 receptor (D3R) has been implicated in mediating various responses to CSs, the current study explored its potential role in modulation of memory consolidation by an avoidance CS. Male Sprague-Dawley rats trained to avoid foot-shocks in a two-way signalled active avoidance task (8 sessions, 30 trials per session, 0.8 mA foot-shock) were pre-treated with the D3R antagonist NGB-2904 (Vehicle, 0.1 or 5 mg/kg) and exposed to the CS immediately after the sample phase of an object recognition memory task. Discrimination ratios were assessed 72 h later. Immediate, but not delayed (6 h), post-sample exposure to the CS enhanced object recognition memory and this effect was blocked by NGB-2904. Control experiments with the beta-noradrenergic receptor antagonist propranolol (10 or 20 mg/kg) and D2R antagonist pimozide (0.2 or 0.6 mg/kg) indicated that NGB-2904 targeted post-training memory consolidation. Exploring the pharmacological selectivity of the NGB-2904 effect, it was found that: 1) 5 mg/kg NGB-2904 blocked conditioned memory modulation produced by post-sample exposure to a “weak” CS (one day of avoidance training) and concurrent stimulation of catecholamine activity by 10 mg/kg bupropion; and 2) post-sample exposure to a “weak” CS and concurrent administration of the D3R agonist 7-OH-DPAT (1 mg/kg) enhanced consolidation of object memory. Finally, because 5 mg/kg NGB-2904 had no effect on modulation by avoidance training in the presence of foot-shocks, the findings herein support the hypothesis that the D3R plays an important role in modulation of memory consolidation by CSs.

Effects of endogenous and exogenous N-acetyl-5-methoxy kynuramine on object recognition memory in male C3H mice

Prevention of dementia is important, because it is a leading cause of disability in elderly people. We previously reported that acute intraperitoneal treatment with N-acetyl-5-methoxy kynuramine (AMK), a melatonin (MEL) metabolite, enhanced long-term object recognition memory in ICR mice, a MEL deficient strain. Despite the presumable availability of AMK for dementia, its effects on cognitive performance have not been elucidated. It is unclear whether endogenous AMK is responsible for modulating long-term memory performance. To address this question, we assessed the effects of endogenous AMK on learning and memory using an object recognition test. C3H mice, a MEL-proficient strain, showed peak MEL levels at zeitgeber times (ZT) 19 and 22. Object recognition memory at ZT20 was superior to that at ZT8. Norharmane (NHM, 100 mg/kg), an indoleamine-2,3-dioxygenase (IDO) inhibitor, prevented the transformation of MEL to AMK, thereby suppressing AMK synthesis at ZT20. NHM (100 mg/kg) and another IDO inhibitor, 1-methyl-L-tryptophan (1-MT, 100 mg/kg), disrupted elevated cognitive performance at ZT20. These data imply that endogenous AMK may play a physiological role in the modulation of cognitive function. We also investigated the effects of pharmacological doses of MEL and AMK on object recognition memory in young C3H mice. MEL administration of 0.1 mg/kg, but not 0.01 mg/kg, enhanced object recognition memory, whereas 0.01 and 1 mg/kg AMK enhanced object recognition memory. Administration of 0.1 and 1 mg/kg AMK also enhanced object recognition memory in old C3H mice. These findings in MEL-proficient mice should be confirmed in other learning and memory tests before encouraging the clinical use of AMK.

Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity

Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.

Melatonin Enhances Object Recognition Memory through Melatonin MT1 and MT2 Receptor-Mediated and Non-Receptor-Mediated Mechanisms in Male Mice

Melatonin (MEL) has been reported to have acute enhancing effects on some aspects of cognition. Recently, we revealed that N1-acetyl-5-methoxyquinuramine (AMK), a brain metabolite of MEL, is much more potent than MEL in converting short-term memory (STM) to long-term memory (LTM) with a single administration immediately after the acquisition trial of the novel object recognition (NOR) task. These data suggest that the memory-enhancing effects of MEL may be mediated by mechanisms independent of the activation of MEL MT1 and MT2 receptors. In the present study, we examined the contribution of MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms to the acute memory-enhancing effects of MEL using NOR task. Mice were administered with either MEL, AMK, or a highly selective MT1/MT2 receptor agonist ramelteon (RAM) immediately after the acquisition trial and the effects of varying doses of these drugs on both STM and LTM performance were compared. We found that both AMK and RAM were more potent than MEL in both facilitating STM and promoting LTM formation. We also found that pretreatment with luzindole, a MT1/MT2 receptor antagonist, markedly suppressed only the effects of RAM. These results suggest that acutely administered MEL enhances NOR memory through both MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms.

Nicotine Enhances Object Recognition Memory via Stimulating α4β2 and α7 Nicotinic Acetylcholine Receptors in the Medial Prefrontal Cortex of Mice.

Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the medial prefrontal cortex (mPFC) is associated with memory, we examined the role of the mPFC in nicotine-induced enhancement of recognition memory using the novel object recognition test in male C57BL/6J mice. Systemic nicotine administration 10 min before training session significantly enhanced object recognition memory in test session that was performed 24 h after the training. Intra-mPFC infusion of mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, 5 min before nicotine administration blocked the effect of nicotine. Additionally, intra-mPFC infusion of dihydro-β-erythroidine, a selective α4β2 nAChR antagonist, or methyllycaconitine, a selective α7 nAChR antagonist, significantly suppressed the nicotine-induced object recognition memory enhancement. Finally, intra-mPFC infusion of nicotine 1 min before the training session augmented object recognition memory in a dose-dependent manner. These findings suggest that mPFC α4β2 and α7 nAChRs mediate the nicotine-induced object recognition memory enhancement.

Nicotine enhances object recognition memory through inhibition of voltage-dependent potassium 7 channels in the medial prefrontal cortex of mice

Nicotine administration enhances object recognition memory. However, target brain regions and cellular mechanisms underlying the nicotine effects remain unclear. In mice, the novel object recognition test revealed that systemic nicotine administration before training enhanced object recognition memory. Moreover, this effect was inhibited by infusion of retigabine, a selective voltage-dependent potassium 7 (Kv7) channel opener, into the medial prefrontal cortex (mPFC) before nicotine administration. Additionally, infusion of XE-991, a selective Kv7 channel blocker, into the mPFC before training enhanced object recognition memory. Therefore, Kv7 channels in the mPFC may be at least partly involved in nicotine-induced enhancement of object recognition memory.

Oral Administration of the Food-Derived Hydrophilic Antioxidant Ergothioneine Enhances Object Recognition Memory in Mice

Oral Administration of the Food-Derived Hydrophilic Antioxidant Ergothioneine Enhances Object Recognition Memory in Mice

Class I HDAC inhibition improves object recognition memory consolidation through BDNF/TrkB pathway in a time-dependent manner

There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC into the insular cortex (IC) and a weak ORM protocol was used to assess temporal expression and function of the BDNF/TrkB pathway in the IC. We found that cortical class I HDAC inhibition enhanced long-term ORM, coincident with a clear peak of BDNF expression at 4 h after acquisition. Furthermore, the tyrosine kinase B (TrkB) receptor blockade at 4 h, but not at 8 h, impaired the consolidation of ORM. These results suggest that histone acetylation regulates the temporal expression of BDNF in cortical circuits potentiating the long-term recognition memory.

Diosgenin content is a novel criterion to assess memory enhancement effect of yam extracts.

Several studies have suggested that some kind of Dioscorea species (yam) or yam-contained herbal medicines have cognitive enhancement effect. However, it has been unknown what is a crucial factor for cognitive enhancement in each Dioscorea species. In this study, we aimed to investigate whether one of the main and brain-penetrating components in yams, diosgenin, can be a novel criterion to assess memory enhancement effect of yam extracts. Although our previous studies showed that administration of diosgenin or diosgenin-rich yam extract enhanced cognitive function in normal mice and healthy humans, we have never evaluated whether the effect depends on diosgenin content or not. Therefore, we compared memory enhancement effects of low diosgenin-contained general yam water extract with diosgenin-rich yam extract on cognitive function in normal mice. We found that unlike diosgenin-rich yam, administration of general yam water extract did not enhance object recognition memory in normal mice. LC-MS/MS analyses revealed that after administration of general yam, diosgenin concentration in the brain did not reach to the effective dose because of the low diosgenin content in the original yam extract. On the other hand, when diosgenin was artificially added into general yam, the extract showed memory enhancement in normal mice and promoted neurite outgrowth in neurons. Our study suggests that diosgenin is actually an active compound in yams for memory enhancement, and diosgenin content can be a criterion for predicting cognitive enhancement effect of yam extracts.

Oral Administration of the Food-Derived Hydrophilic Antioxidant Ergothioneine Enhances Object Recognition Memory in Mice.

The enhancement of learning and memory through food-derived ingredients is of great interest to healthy individuals as well as those with diseases. Ergothioneine (ERGO) is a hydrophilic antioxidant highly contained in edible golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), and systemically absorbed by its specific transporter, carnitine/organic cation transporter OCTN1/SLC22A4. This study aims to examine the possible enhancement of object recognition memory by oral administration of ERGO in normal mice. Novel object recognition test, spatial recognition test, LC-MS/MS, Golgi staining, neuronal culture, western blotting, immunocytochemistry, and quantitative RT-PCR were utilized. After oral administration of ERGO (at a dose of 1-50 mg/kg) three times per week for two weeks in ICR mice, the novel object recognition test revealed a longer exploration time for the novel object than for the familiar object. After oral administration of ERGO, the spatial recognition test also revealed a longer exploration time for the spatially moved object than the unmoved one in mice fed ERGO-free diet. The discrimination index was significantly higher in the ERGO-treated group than the control in both behavioral tests. ERGO administration led to an increase in its concentration in the plasma and hippocampus. The systemic concentration reached was relevant to those found in humans after oral ERGO administration. Golgi staining revealed that ERGO administration increased the number of matured spines in the hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I. This elevation of synapsin I was inhibited by the tropomyosin receptor kinase inhibitor, K252a. Treatment with ERGO also increased the expression of neurotrophin-3 and -5, and phosphorylated mammalian target of rapamycin in hippocampal neurons. Oral intake of ERGO may enhance object recognition memory at its plasma concentration achievable in humans, and this enhancement effect could occur, at least in part, through the promotion of neuronal maturation in the hippocampus.

Memory Enhancement by Oral Administration of Extract of Eleutherococcus senticosus Leaves and Active Compounds Transferred in the Brain.

The pharmacological properties of Eleutherococcus senticosus leaf have not been clarified although it is taken as a food item. In this study, the effects of water extract of Eleutherococcus senticosus leaves on memory function were investigated in normal mice. Oral administration of the extract for 17 days significantly enhanced object recognition memory. Compounds absorbed in blood and the brain after oral administration of the leaf extract were detected by LC-MS/MS analyses. Primarily detected compounds in plasma and the cerebral cortex were ciwujianoside C3, eleutheroside M, ciwujianoside B, and ciwujianoside A1. Pure compounds except for ciwujianoside A1 were administered orally for 17 days to normal mice. Ciwujianoside C3, eleutheroside M, and ciwujianoside B significantly enhanced object recognition memory. These results demonstrated that oral administration of the leaf extract of E. senticosus enhances memory function, and that active ingredients in the extract, such as ciwujianoside C3, eleutheroside M, and ciwujianoside B, were able to penetrate and work in the brain. Those three compounds as well as the leaf extract had dendrite extension activity against primary cultured cortical neurons. The effect might relate to memory enhancement.

Cocaine, nicotine, and their conditioned contexts enhance consolidation of object memory in rats.

To test the hypothesis that drugs of abuse and their conditioned stimuli (CSs) enhance memory consolidation, the effects of post-training exposure to cocaine and nicotine were compared to the effects of post-training exposure to contextual stimuli that were paired with the effects of these drugs. Using the object recognition (OR) task, it was first demonstrated that both 10 and 20 mg/kg cocaine, and 0.2 and 0.4 mg/kg nicotine, enhanced recognition memory when administered immediately after, but not 6 h after the sample phase. To establish the drug CSs, rats were confined for 2 h in a chamber (the CS+) after injections of 20 mg/kg cocaine, or 0.4 mg/kg nicotine, and in another chamber (the CS−) after injections of vehicle. This was repeated over 10 d (5 drug/CS+ and 5 vehicle/CS− pairings in total). At the end of this conditioning period, when tested in a drug-free state, rats displayed conditioned hyperactivity in the CS+ relative to the CS−. More important, immediate, but not delayed, post-sample exposure to the cocaine CS+, or nicotine CS+, enhanced OR memory. Therefore, this study reports for the first time that contextual stimuli paired with cocaine and nicotine, like the drugs themselves, have the ability to enhance memory consolidation.

Oral administration of food-derived hydrophilic antioxidant ergothioneine enhances object recognition memory and promotes neuronal maturation in murine hippocampus

Oral administration of food-derived hydrophilic antioxidant ergothioneine enhances object recognition memory and promotes neuronal maturation in murine hippocampus

Aggrecan Directs Extracellular Matrix-Mediated Neuronal Plasticity.

In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan using a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin-expressing inhibitory interneurons toward a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory.SIGNIFICANCE STATEMENT The study provides the first direct evidence of aggrecan as the main functional constituent and orchestrator of perineuronal nets (PNNs), and that loss of PNNs by aggrecan removal induces a permanent state of critical period-like plasticity. Loss of aggrecan ablates the PNN structure, resulting in invoked juvenile plasticity in the visual cortex and enhanced object recognition memory.

Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent

In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20–30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery.