Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.

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BackgroundAyahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures.MethodsUsing 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose.ResultsMagnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the “nonjudging” subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later.ConclusionsThese results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca.

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

IntroductionAyahuasca is a South American psychotropic plant tea traditionally used in Amazonian shamanism. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine oxidase-inhibiting properties. Increasing evidence from anecdotal reports and open-label studies indicates that ayahuasca may have therapeutic effects in treatment of substance use disorders and depression. A recent study on the psychological effects of ayahuasca found that the tea reduces judgmental processing and inner reactivity, classic goals of mindfulness psychotherapy. Another psychological facet that could potentially be targeted by ayahuasca is creative divergent thinking. This mode of thinking can enhance and strengthen psychological flexibility by allowing individuals to generate new and effective cognitive, emotional, and behavioral strategies. The present study aimed to assess the potential effects of ayahuasca on creative thinking.MethodsWe visited two spiritual ayahuasca workshops and invited participants to conduct creativity tests before and during the acute effects of ayahuasca. In total, 26 participants consented. Creativity tests included the “pattern/line meanings test” (PLMT) and the “picture concept test” (PCT), both assessing divergent thinking and the latter also assessing convergent thinking.ResultsWhile no significant effects were found for the PLMT, ayahuasca intake significantly modified divergent and convergent thinking as measured by the PCT. While convergent thinking decreased after intake, divergent thinking increased.ConclusionsThe present data indicate that ayahuasca enhances creative divergent thinking. They suggest that ayahuasca increases psychological flexibility, which may facilitate psychotherapeutic interventions and support clinical trial initiatives.

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Highlights d Exposure to the psychedelic drug DOI results in enduring molecular adaptations d Post-acute DOI unveils phenotypes akin to antidepressant adaptations d Concurrent occurrence of synaptic plasticity mediated via 5-HT