Significance: Higher-level cognitive processes strongly depend on a complex interplay between the mediodorsal thalamus and the prefrontal cortex. Alteration of thalamofrontal connectivity has been involved in schizophrenia. Prefrontal serotonin (5-HT)_2Areceptors play an essential role in cortical network activity but the mechanism underlying their modulation of synaptic plasticity remains unexplored. Here, we demonstrate—to our knowledge for the first time—a physiological role of presynaptic 5-HT_2Areceptors in the NMDA-operated induction of temporal-dependent plasticity at thalamocortical synapses. We show that 5-HT_2A^−/−mice exhibit alterations in plasticity and associative memory that are rescued by re-expressing receptors in the thalamus. These findings highlight a critical role of presynaptic 5-HT_2Areceptor dysfunction in cognitive symptoms observed in schizophrenia.

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-HT_2A receptor (5-HT_2AR), 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-HT_2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT_2AR 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-HT_2AR 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-HT_2A^−/− mice, whereas psilocybin was still effective. Moreover, neither 5-HT_1AR blockade nor dopamine D₁ or D₂ receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT_2A^−/− mice. Collectively, these findings indicate that 5-HT_2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

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-HT_2A 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-HT_2A 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-HT_2A receptor-deficient mice, is rescued by viral expression of 5-HT_2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT_2A 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.

There is an urgent need for efficient and innovative therapies to treat brain disorders such as psychiatric and neurodegenerative diseases. Immunotherapies have proved to be efficient in many medical areas, but have not been considered to treat brain diseases due to the poor brain penetration of immunoglobulins^1,2. Here we developed a bivalent biparatopic antibody, made of two camelid heavy-chain antibodies (called nanobodies)³, one binding to, and the other potentiating the activity of, homodimeric metabotropic glutamate receptor 2. We show that this bivalent nanobody, given peripherally, reaches the brain and corrects cognitive deficits in two preclinical mouse models with endophenotypes resulting from NMDA receptor hypofunction. Notably, these in vivo effects last for at least 7 days after a single intraperitoneal injection and are maintained after subchronic treatment. Our results establish a proof of concept that nanobodies can target brain receptors, and pave the way for nanobody-based therapeutic strategies for the treatment of brain disorders.