Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A-/- mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A-/- mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

Impact of 5-HT6 Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles.

The serotonin (5-HT)6 receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT6 receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT6 receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor's coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence.

Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development.

The serotonin 5-HT6 receptor (5-HT6R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin.

Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice.

Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/- mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/- mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

The Complex Formed by Group I Metabotropic Glutamate Receptor (mGluR) and Homer1a Plays a Central Role in Metaplasticity and Homeostatic Synaptic Scaling.

G-protein-coupled receptors can be constitutively activated following physical interaction with intracellular proteins. The first example described was the constitutive activation of Group I metabotropic glutamate receptors (mGluR: mGluR1,5) following their interaction with Homer1a, an activity-inducible early-termination variant of the scaffolding protein Homer that lacks dimerization capacity (Ango et al., 2001). Homer1a disrupts the links, maintained by the long form of Homer (cross-linking Homers), between mGluR1,5 and the Shank-GKAP-PSD-95-ionotropic glutamate receptor network. Two characteristics of the constitutive activation of the Group I mGluR-Homer1a complex are particularly interesting: (1) it affects a large number of synapses in which Homer1a is upregulated following enhanced, long-lasting neuronal activity; and (2) it mainly depends on Homer1a protein turnover. The constitutively active Group I mGluR-Homer1a complex is involved in the two main forms of non-Hebbian neuronal plasticity: "metaplasticity" and "homeostatic synaptic scaling," which are implicated in a large series of physiological and pathologic processes. Those include non-Hebbian plasticity observed in visual system, synapses modulated by addictive drugs (rewarded synapses), chronically overactivated synaptic networks, normal sleep, and sleep deprivation.

Novel and atypical pathways for serotonin signaling.

Serotonin (5-HT) appeared billions of years before 5-HT receptors and synapses. It is thus not surprising that 5-HT can control biological processes independently of its receptors. One example is serotonylation, which consists of covalent binding of 5-HT to the primary amine of glutamine. Over the past 20 years, serotonylation has been involved in the regulation of many signaling mechanisms. One of the most striking examples is the recent evidence that serotonylation of histone H3 constitutes an epigenetic mark. However, the pathophysiological role of histone H3 serotonylation remains to be discovered. All but one of the 5-HT receptors are G-protein-coupled receptors (GPCRs). The signaling pathways they control are finely tuned, and new, unexpected regulatory mechanisms are being uncovered continuously. Some 5-HT receptors (5-HT2C, 5-HT4, 5-HT6, and 5-HT7) signal through mechanisms that require neither G-proteins nor ß-arrestins, the two classical and almost universal GPCR signal transducers. 5-HT6 receptors are constitutively activated via their association with intracellular GPCR-interacting proteins (GIPs), including neurofibromin 1, cyclin-dependent kinase 5 (Cdk5), and G-protein-regulated inducer of neurite outgrowth 1 (GPRIN1). Interactions of 5-HT6 receptor with Cdk5 and GPRIN1 are not concomitant but occur sequentially and play a key role in dendritic tree morphogenesis. Furthermore, 5-HT6 receptor-mediated G-protein signaling in neurons is different in the cell body and primary cilium, where it is modulated by smoothened receptor activation. Finally, 5-HT2A receptors form heteromers with mGlu2 metabotropic glutamate receptors. This heteromerization results in a specific phosphorylation of mGlu2 receptor on a serine residue (Ser843) upon agonist stimulation of 5-HT2A or mGlu2 receptor. mGlu2 receptor phosphorylation on Ser843 is an essential step in engagement of Gi/o signaling not only upon mGlu2 receptor activation but also following 5-HT2A receptor activation, and thus represents a key molecular event underlying functional crosstalk between both receptors.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

Early 5-HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.

Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT6 receptor-operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9-tetrahydrocannabinol (THC) to mice during adolescence induces a long-lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long-term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5-HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5-HT6 receptor-operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5-HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers.

Dynamic interactions of the 5-HT6 receptor with protein partners control dendritic tree morphogenesis.

The serotonin (5-hydroxytrypatmine) receptor 5-HT6 (5-HT6R) has emerged as a promising target to alleviate the cognitive symptoms of neurodevelopmental diseases. We previously demonstrated that 5-HT6R finely controls key neurodevelopmental steps, including neuronal migration and the initiation of neurite growth, through its interaction with cyclin-dependent kinase 5 (Cdk5). Here, we showed that 5-HT6R recruited G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) through a Gs-dependent mechanism. Interactions between the receptor and either Cdk5 or GPRIN1 occurred sequentially during neuronal differentiation. The 5-HT6R-GPRIN1 interaction enhanced agonist-independent, receptor-stimulated cAMP production without altering the agonist-dependent response in NG108-15 neuroblastoma cells. This interaction also promoted neurite extension and branching in NG108-15 cells and primary mouse striatal neurons through a cAMP-dependent protein kinase A (PKA)-dependent mechanism. This study highlights the complex allosteric modulation of GPCRs by protein partners and demonstrates how dynamic interactions between GPCRs and their protein partners can control the different steps of highly coordinated cellular processes, such as dendritic tree morphogenesis.

The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies.

The serotonin (5-HT)6 receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively located in the primary cilium of neurons. The 5-HT6 receptor continues to raise particular interest for neuropharmacologists, given the pro-cognitive effects of antagonists in a wide range of cognitive impairment paradigms in rodents and human. The 5-HT6 receptor also finely controls key neuro-developmental processes including neuron migration and differentiation. However, its influence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggesting alternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT6 receptor one of the G protein-coupled receptors with the most extensively characterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, are finely modulated by several receptor partners. They demonstrated that prefrontal 5-HT6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT6-mTOR pathway in temporal epilepsy. Finally, they revealed that the receptor activates Cdk5 signaling in an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key role in the migration of neurons and neurite growth. These new receptor-operated signaling mechanisms should be considered in the future development of drugs acting on 5-HT6 receptors. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Donecopride, a Swiss army knife with potential against Alzheimer's disease.

BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD). EXPERIMENTAL APPROACH: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-ß peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-ß peptides on neuronal survival and neurite formation determined in vitro. KEY RESULTS: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-ß peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS AND IMPLICATIONS: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.

5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling.

The serotonin 5-HT2A and glutamate mGlu2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A-/- mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.

Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses.

The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT2A receptor-deficient mice, is rescued by viral expression of 5-HT2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser880 and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin.

Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT4 receptors (5-HT4Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-ß peptide (Aß) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HT4R agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HT4R as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action.

Phosphorylation of ß-arrestin2 at Thr383 by MEK underlies ß-arrestin-dependent activation of Erk1/2 by GPCRs.

In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs), ß-arrestins are essential scaffolds linking GPCRs to Erk1/2 signaling. However, their role in GPCR-operated Erk1/2 activation differs between GPCRs and the underlying mechanism remains poorly characterized. Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a ß-arrestin-dependent mechanism, promotes MEK-dependent ß-arrestin2 phosphorylation at Thr383, a necessary step for Erk recruitment to the receptor/ß-arrestin complex and Erk activation. Likewise, Thr383 phosphorylation is involved in ß-arrestin-dependent Erk1/2 stimulation elicited by other GPCRs such as ß2-adrenergic, FSH and CXCR4 receptors, but does not affect the ß-arrestin-independent Erk1/2 activation by 5-HT4 receptor. Collectively, these data show that ß-arrestin2 phosphorylation at Thr383 underlies ß-arrestin-dependent Erk1/2 activation by GPCRs.

Physical and functional interactions between the serotonin transporter and the neutral amino acid transporter ASCT2.

The activity of serotonergic systems depends on the reuptake of extracellular serotonin via its plasma membrane serotonin [5-HT (5-hydroxytryptamine)] transporter (SERT), a member of the Na(+)/Cl(-)-dependent solute carrier 6 family. SERT is finely regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins. The majority of previously identified SERT partners that control its functional activity are soluble proteins, which bind to its intracellular domains. SERT also interacts with transmembrane proteins, but its association with other plasma membrane transporters remains to be established. Using a proteomics strategy, we show that SERT associates with ASCT2 (alanine-serine-cysteine-threonine 2), a member of the solute carrier 1 family co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane. Co-expression of ASCT2 with SERT in HEK (human embryonic kidney)-293 cells affects glycosylation and cell-surface localization of SERT with a concomitant reduction in its 5-HT uptake activity. Conversely, depletion of cellular ASCT2 by RNAi enhances 5-HT uptake in both HEK-293 cells and primary cultured mesencephalon neurons. Mimicking the effect of ASCT2 down-regulation, treatment of HEK-293 cells and neurons with the ASCT2 inhibitor D-threonine also increases 5-HT uptake. Moreover, D-threonine does not enhance further the maximal velocity of 5-HT uptake in cells depleted of ASCT2. Collectively, these findings provide evidence for a complex assembly involving SERT and a member of another solute carrier family, which strongly influences the subcellular distribution of SERT and the reuptake of 5-HT.

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning.

Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.