Cage effects on synaptic plasticity and its modulation in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is characterized by impairments in executive function including different types of learning and memory. Long-term potentiation (LTP), thought to underlie the formation of memories, has been studied in the Fmr1 mouse model of FXS. However, there have been many discrepancies in the literature with inconsistent use of littermate and non-littermate Fmr1 knockout (KO) and wild-type (WT) control mice. Here, the influence of the breeding strategy (cage effect) on short-term potentiation (STP), LTP, contextual fear conditioning (CFC), expression of N-methyl-d-aspartate receptor (NMDAR) subunits and the modulation of NMDARs, were examined. The largest deficits in STP, LTP and CFC were found in KO mice compared with non-littermate WT. However, the expression of NMDAR subunits was unchanged in this comparison. Rather, NMDAR subunit (GluN1, 2A, 2B) expression was sensitive to the cage effect, with decreased expression in both WT and KO littermates compared with non-littermates. Interestingly, an NMDAR-positive allosteric modulator, UBP714, was only effective in potentiating the induction of LTP in non-littermate KO mice and not the littermate KO mice. These results suggest that commonly studied phenotypes in Fmr1 KOs are sensitive to the cage effect and therefore the breeding strategy may contribute to discrepancies in the literature.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Incremental induction of NMDAR-STP and NMDAR-LTP in the CA1 area of ventral hippocampal slices relies on graded activation of discrete NMDA receptors.

N-methyl-d-aspartate receptor (NMDAR)-dependent short- and long-term types of potentiation (STP and LTP, respectively) are frequently studied in the CA1 area of dorsal hippocampal slices (DHS). Far less is known about the NMDAR dependence of STP and LTP in ventral hippocampal slices (VHS), where both types of potentiation are smaller in magnitude than in the DHS. Here, we first briefly review our knowledge about the NMDAR dependence of STP and LTP and some other forms of synaptic plasticity. We then show in new experiments that the decay of NMDAR-STP in VHS, similar to dorsal hippocampal NMDAR-STP, is not time- but activity-dependent. We also demonstrate that the induction of submaximal levels of NMDAR-STP and NMDAR-LTP in VHS differs from the induction of saturated levels of plasticity in terms of their sensitivity to subunit-preferring NMDAR antagonists. These data suggest that activation of distinct NMDAR subtypes in a population of neurons results in an incremental increase in the induction of different phases of potentiation with changing sensitivity to pharmacological agents. Differences in pharmacological sensitivity, which arise due to differences in the levels of agonist-evoked biological response, might explain the disparity of the results concerning NMDAR subunit involvement in the induction of NMDAR-dependent plasticity.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

The response to fasting and refeeding reveals functional regulation of lipoprotein lipase proteoforms.

Lipoprotein lipase (LPL) is responsible for the intravascular catabolism of triglyceride-rich lipoproteins and plays a central role in whole-body energy balance and lipid homeostasis. As such, LPL is subject to tissue-specific regulation in different physiological conditions, but the mechanisms of this regulation remain incompletely characterized. Previous work revealed that LPL comprises a set of proteoforms with different isoelectric points, but their regulation and functional significance have not been studied thus far. Here we studied the distribution of LPL proteoforms in different rat tissues and their regulation under physiological conditions. First, analysis by two-dimensional electrophoresis and Western blot showed different patterns of LPL proteoforms (i.e., different pI or relative abundance of LPL proteoforms) in different rat tissues under basal conditions, which could be related to the tissue-specific regulation of the enzyme. Next, the comparison of LPL proteoforms from heart and brown adipose tissue between adults and 15-day-old rat pups, two conditions with minimal regulation of LPL in these tissues, yielded virtually the same tissue-specific patterns of LPL proteoforms. In contrast, the pronounced downregulation of LPL activity observed in white adipose tissue during fasting is accompanied by a prominent reconfiguration of the LPL proteoform pattern. Furthermore, refeeding reverts this downregulation of LPL activity and restores the pattern of LPL proteoforms in this tissue. Importantly, this reversible proteoform-specific regulation during fasting and refeeding indicates that LPL proteoforms are functionally diverse. Further investigation of potential differences in the functional properties of LPL proteoforms showed that all proteoforms exhibit lipolytic activity and have similar heparin-binding affinity, although other functional aspects remain to be investigated. Overall, this study demonstrates the ubiquity, differential distribution and specific regulation of LPL proteoforms in rat tissues and underscores the need to consider the existence of LPL proteoforms for a complete understanding of LPL regulation under physiological conditions.

Irisin as a Novel Biomarker of Subclinical Atherosclerosis in Severe Obesity.

Severe obesity (SO) can accelerate atherosclerosis and the onset of acute cardiovascular events. The diagnosis of atherosclerosis in the context of a high body mass index (BMI) can be challenging, making the identification of biomarkers clinically relevant. We aimed to assess the usefulness of irisin as a biomarker for subclinical atherosclerosis in participants with SO. This prospective observational study included 61 participants undergoing bariatric surgery for SO, defined as a BMI >40 kg/m2 or >35 kg/m2 with at least one comorbidity. Atherosclerotic plaques were detected by ultrasound. Plasma samples were obtained 1 month before and at 6 and 12 months after bariatric surgery to measure irisin by ELISA. Additionally, subcutaneous samples of adipose tissue were taken and genotyped to identify irisin polymorphism rs3480. Irisin levels were positively correlated with BMI (r = 0.23, p = 0.0064), negatively correlated with atheroma-related parameters (e.g., carotid intima-media thickness), and lower in subjects with atheroma (p < 0.0002). Irisin also showed good overall accuracy for discriminating plaque presence (AUC, 0.81; 95% CI, 0.6956-0.9156). However, the rs3480 polymorphism correlated with neither the irisin levels nor the presence of atheromas. Iirisin could identify subclinical atherosclerosis in SO and might facilitate clinical diagnosis.

Pharmacological characterization of a novel negative allosteric modulator of NMDA receptors, UBP792.

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a subtype of ionotropic glutamate receptor with important roles in CNS function. Since excessive NMDAR activity can lead to neuronal cell death and epilepsy, there is interest in developing NMDAR negative allosteric modulators (NAMs) as neuroprotective agents. In this study, we characterize the inhibitory properties of a novel NMDAR antagonist, UBP792. This compound displays partial subtype-selectivity by having a varied maximal inhibition of GluN2A-, GluN2B-, GluN2C-, and GluN2D-containing receptors (52%, 70%, 87%, 89%, respectively) with IC50s 4-10 µM. UBP792 inhibited NMDAR responses by reducing l-glutamate and glycine potencies and efficacies. Consistent with non-competitive inhibition, increasing agonist concentrations 30-fold did not reduce UBP792 potency. UBP792 inhibition was also not competitive with the structurally-related positive allosteric modulator (PAM) UBP684. UBP792 activity was voltage-independent, unaffected by GluN1's exon-5, and reduced at low pH (except for GluN1/GluN2A receptors which were more sensitive at acidic pH). UBP792 binding appeared independent of agonist binding and may be entering the plasma membrane to gain access to its binding site. Inhibition by UBP792 is reduced when the ligand-binding domain (LBD) of the GluN2 subunit, but not that of the GluN1 subunit, is cross-linked in the closed-cleft, activated conformation. Thus, UBP792 may be inhibiting by stabilizing an open GluN2-LBD cleft associated with channel inactivation or by stabilizing downstream closed channel conformations allosterically-coupled to the GluN2-LBD. These findings further expand the repertoire displayed by NMDAR NAMs thus expanding the opportunities for developing NMDAR modulators with the most appropriate selectivity and physiological actions for specific therapeutic indications.

Multiple roles of GluN2D-containing NMDA receptors in short-term potentiation and long-term potentiation in mouse hippocampal slices.

The GluN2 subunits of N-methyl-d-aspartate receptors (NMDARs) are key drivers of synaptic plasticity in the brain, where the particular GluN2 composition endows the NMDAR complex with distinct pharmacological and physiological properties. Compared to GluN2A and GluN2B subunits, far less is known about the role of the GluN2D subunit in synaptic plasticity. In this study, we have used a GluN2C/2D selective competitive antagonist, UBP145, in combination with a GluN2D global knockout (GluN2D KO) mouse line to study the contribution of GluN2D-containing NMDARs to short-term potentiation (STP) and long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices. We made several distinct observations: First, GluN2D KO mice have higher levels of LTP compared to wild-type (WT) mice, an effect that was occluded by blockade of GABA receptor-mediated inhibition or by using a strong LTP induction protocol. Second, UBP145 partially inhibited LTP in WT but not GluN2D KO mice. Third, UBP145 inhibited a component of STP, termed STP2, in WT but not GluN2D KO mice. Taken together, these findings suggest an involvement for GluN2D-containing NMDARs in both STP and LTP in mouse hippocampus.

Synthesis and pharmacological characterisation of arctigenin analogues as antagonists of AMPA and kainate receptors.

(-)-Arctigenin and a series of new analogues have been synthesised and then tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors expressed in HEK293 cells using a Ca2+ influx assay. In general, these compounds showed antagonist activity at both receptors with greater activity evident at AMPARs. Schild analysis indicates that a spirocyclic analogue 6c acts as a non-competitive antagonist. Molecular docking studies in which 6c was docked into the X-ray crystal structure of the GluA2 tetramer suggest that (-)-arctigenin and its analogues bind in the transmembrane domain in a similar manner to the known AMPA receptor non-competitive antagonists GYKI53655 and the antiepileptic drug perampanel. The arctigenin derivatives described herein may serve as novel leads for the development of drugs for the treatment of epilepsy.

Effect of bariatric surgery on inflammation and endothelial dysfunction as processes underlying subclinical atherosclerosis in morbid obesity.

BACKGROUND: Inflammation and endothelial dysfunction are associated with morbid obesity (MO) and atherosclerosis. OBJECTIVE: To evaluate inflammation and endothelial function as the initial mechanisms underlying subclinical atherosclerosis in patients with MO, with and without atheromas, and their evolution after bariatric surgery (BS). SETTING: Arnau de Vilanova University Hospital and University of Barcelona. METHODS: Plasma samples from 66 patients with MO were obtained before BS and 6 and 12 months after BS. Patients were divided into 2 groups based on the presence of atheromatous plaques (detected by ultrasound imaging). RESULTS: Inflammation was increased as demonstrated by changes in the levels of fibroblast growth factor 21, adiponectin, leptin, interleukin 6, tumor growth factor α, nonesterified free fatty acids, lipoprotein(a) and C-reactive protein (CRP). Endothelial dysfunction was characterized by impaired angiogenesis (measured through angiopoietin 1 and 2 and brain-derived neurotrophic factor), vascular function (changes in endothelin 1 and thrombomodulin levels), and diapedesis (changes in intercellular and vascular cell adhesion molecules, and E- and P-selectins). Both mechanisms occurred regardless of the presence of atheromas. BS ameliorated both processes even in patients who already had subclinical atherosclerosis. However, CRP, thrombomodulin, and P-selectin levels were higher in patients with atheromas. CONCLUSIONS: Endothelial dysfunction and inflammation were detected before the appearance of structural changes in vessel walls on ultrasonography images. BS might prevent or slow atherogenesis in the early stages by breaking the vicious circle between inflammation and endothelial dysfunction. CRP, thrombomodulin, and P-selectin may have a critical role in plaque development and, together with the study of endothelial dysfunction, might be useful in assessing early atherosclerosis and its evolution after BS.

Effect of bariatric surgery in the evolution of oxidative stress depending on the presence of atheroma in patients with morbid obesity.

BACKGROUND: Morbid obesity is associated with accelerated atherosclerosis, a chronic vascular disease related to oxidative stress (OS) and endothelial dysfunction. OBJECTIVES: We aimed to evaluate the effect of bariatric surgery (BS) on oxidative stress as a cardiovascular risk factor in patients with and without atheromatous plaques. SETTING: Arnau de Vilanova University Hospital and University of Barcelona. METHODS: Plasma samples from 66 patients with morbid obesity were obtained before BS and 6 and 12 months after. Patients were divided into 2 groups based on the presence of atheromatous plaques (detected by ultrasonography). OS parameters were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with morbid obesity had OS independently of the presence of an atheroma, but oxidized low-density lipoprotein levels were higher in patients with plaques throughout the study (P = .0430). After surgery, oxidized low-density lipoprotein and malondialdehyde levels decreased significantly (P < .0001 in both cases). At the beginning of the study, antioxidant enzyme levels were the same between the groups. After surgery, paraoxonase 1 levels were increased (P < .0001) in the group without plaque, being significantly higher (P = .0147). Superoxide dismutase 2 levels were only decreased in patients without plaque (P < .0010), while catalase activity was higher in patients with plaque. CONCLUSIONS: Morbid obesity may lead to chronic OS, which increases predisposition to atherogenesis. BS improves the antioxidant profile and reduces OS and co-morbidities in both groups. However, the benefits are greater for patients without plaque. Therefore, BS may prevent atheroma formation and also could prevent plaque rupture by decreasing OS.

Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.

N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.

Seasonal variation of body weight loss after bariatric surgery.

Seasonal variations have been described in humans in several variables such as sleep, mood, appetite, food preferences, or body weight. We hypothesized that these variations could also influence the decrease in body weight rate in patients submitted to body weight loss interventions. Thus, here we tested the variations of weight loss according to the time of the year the surgery took place in a group patients (n = 1322) submitted to bariatric surgery in the Hospital Universitari de la Vall d'Hebron in Barcelona (geographical coordinates: 41°25'41″N 2°8'32″E). For the analysis, the percentage of total body weight loss (%TWL), excess body weight loss (%EWL) and percentage of body mass index loss (%BMIL) were calculated at 3 (n = 1255), 6 (n = 1172), 9 (n = 1002), and 12 months (n = 1076) after surgery. For %EWL and %BMIL a statistically significant seasonal variation was detected when the variables were calculated at 3 months, but not at the other times, with more weight loss in summer-fall. However, seasonal variations were not detected for %TWL (p = 0.09). The mean amplitude of the seasonal rhythm for %EWL was of 1.8%, while for the rhythm of %BMIL was 0.7%. Moreover, a second peak was detected in January-February modulating the seasonal rhythm of the two variables. Results confirm seasonal variations in humans and indicate that short term responses to weight loss can be modulated by the time of year.

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid.

The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC50s of 1.4 µM and 2.9 µM, respectively, for inhibition of GluN2D but showed only 70-80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.

Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.

Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.

Seasonal variations of changes in lipid and glucidic variables after bariatric surgery.

Seasonality is a phenomenon that is characterized by changes over the year in sleep, mood, behaviour, appetite and body weight. In humans, seasonal variations have been found in certain variables, such as lipid variables and body mass index. We hypothesize that this rhythm could influence the expected variation of the levels of biochemical variables in cases of body weight loss. Thus, the goal of this study was to observe whether the time of year in which bariatric surgery (BS) took place modulated the changes in several variables related to glucidic and lipid metabolism. Blood samples were obtained from 24 women and 10 men before BS and 1 and 3 months after BS. We calculated the percentage of variation that occurred for each individual and for each variable as a function of the time of the year. Data were adjusted to a 12-month period sinusoidal curve, with significance being set at p < 0.05. The results showed that almost all of the studied variables changed due to the BS according to a seasonal rhythm. Most of the variables showed a decrease that was most prominent in winter. In the cases of body mass index (BMI), adrenocorticotropin hormone (ACTH), and cortisol, the highest variation occurred in winter. Insulin and cholesterol in high-density lipoproteins (cHLD) variations were higher in springtime. Glucose variation showed a decrease after surgery with acrophase in summer-fall and plasminogen activator inhibitor-1 (PAI-1) and homeostatic model assessment-insulin resistance (HOMA-IR) in spring-summer. Ghrelin levels showed increases with a rhythm of variation with an acrophase in summer-fall. The seasonal rhythm found in this study fits nearly with the inverse of the endogenous circannual rhythm of the variables studied. The time of the year when the highest variation takes place is related to the circannual rhythm of the variable. The results agree with the manifestation of seasonal rhythm in human biochemical variables, which are reflected in the responses to weight loss after BS.

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators.

N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2's M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.

Assembly and Trafficking of Homomeric and Heteromeric Kainate Receptors with Impaired Ligand Binding Sites.

Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) mediating excitatory synaptic transmission. Cell surface expressed KARs modulate the excitability of neuronal networks. The transfer of iGluRs from the endoplasmic reticulum (ER) to the cell surface requires occupation of the agonist binding sites. Here we used molecular modelling to produce a range of ligand binding domain (LBD) point mutants of GluK1-3 KAR subunits with and without altered agonist efficacy to further investigate the role of glutamate binding in surface trafficking and activation of homomeric and heteromeric KARs using endoglycosidase digestion, cell surface biotinylation and imaging of changes in intracellular Ca2+ concentration [Ca2+]i. Mutations of conserved amino acid residues in the LBD that disrupt agonist binding to GluK1-3 (GluK1-T675V, GluK2-A487L, GluK2-T659V and GluK3-T661V) reduced both the total expression levels and cell surface delivery of all of these mutant subunits compared to the corresponding wild type in transiently transfected human embryonic kidney 293 (HEK293) cells. In contrast, the exchange of non-conserved residues in the LBD that convert antagonist selectivity of GluK1-3 (GluK1-T503A, GluK2-A487T, GluK3-T489A, GluK1-N705S/S706N, GluK2-S689N/N690S, GluK3-N691S) did not alter the biosynthesis and trafficking of subunit proteins. Co-assembly of mutant GluK2 with an impaired LBD and wild type GluK5 subunits enables the cell surface expression of both subunits. However, [Ca2+]i imaging indicates that the occupancy of both GluK2 and GluK5 LBDs is required for the full activation of GluK2/GluK5 heteromeric KAR channels.

Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity.

Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 µM) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value ∼ 15 µM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.