Role of the serotonin receptor 6 in cortical circuit formation

The formation of a laminar structure such as the mammalian neocortex relies on the coordinated migration of different subtypes of excitatory pyramidal neurons in specific layers. Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration. Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR). Here, we investigated the role of the 5-HT6R in the positioning and migration of pyramidal neurons during mouse corticogenesis. We report that constitutive expression of the 5-HT6R controls pyramidal neuron migration through an agonist-independent mechanism that requires cyclin-dependent kinase 5 activity. These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration

5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits

5-HT6 receptor (5-HT6R) is a G protein-coupled receptor that has recently emerged as a new regulator of neural development. In addition to the canonical Gs adenylyl cyclase pathway, recent proteomics approaches reveal that 5-HT6R is able to engage key developmental signaling pathways controlling neuronal circuit formation, neuronal connectivity, and psychiatric-relevant behaviors. For example, at early stages of neuronal development, expression of 5-HT6R constitutively regulates the activity of the cyclin-dependent kinase (Cdk)5 and, through this mechanism, controls cellular processes involved in circuit formation, including neuronal migration and neurite outgrowth. In addition to the Cdk5 pathway, 5-HT6R modulates a variety of key developmental targets such as Fyn, Jab1, and mammalian target of rapamycin (mTOR). Engagement of developmental pathways through 5-HT6R pharmacological manipulation has led to interesting new therapeutic perspectives in the field of psychiatric-related disorders. Indeed, 5-HT6R blockade can rescue a pathological overactivation of the mTOR pathway induced by early life insults in rodents and normalizes the associated social and episodic memory deficits. Here, we review recent evidence supporting the notion that 5-HT6R is at the interface of key developmental signaling pathways and a novel actor in the orchestration of neural circuit formation

The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism

The formation of a laminar structure such as the mammalian neocortex relies on the coordinated migration of different subtypes of excitatory pyramidal neurons in specific layers. Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration. Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR). Here, we investigated the role of 5-HT6R in the positioning and migration of pyramidal neurons during mouse corticogenesis. We report that constitutive expression of 5-HT6R controls pyramidal neuron migration through an agonist-independent mechanism that requires Cdk5 activity. These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration

Transient Cell-intrinsic Activity Regulates the Migration and Laminar Positioning of Cortical Projection Neurons

Neocortical microcircuits are built during development and require the coordinated assembly of excitatory glutamatergic projection neurons (PNs) into functional networks. Neuronal migration is an essential step in this process. In addition to cell-intrinsic mechanisms, external cues including neurotransmitters regulate cortical neuron migration, suggesting that early activity could influence this process. Here, we aimed to investigate the role of cell-intrinsic activity in migrating PNs in vivo using a designer receptor exclusively activated by a designer drug (DREADD) chemogenetic approach. In utero electroporation was used to specifically express the human M3 muscarinic cholinergic Gq-coupled receptor (hM3Dq) in PNs and calcium activity, migratory dynamics, gene expression, and laminar positioning of PNs were assessed following embryonic DREADD activation. We found that transient embryonic DREADD activation induced premature branching and transcriptional changes in migrating PNs leading to a persistent laminar mispositioning of superficial layer PNs into deep cortical layers without affecting expression of layer-specific molecular identity markers. In addition, live imaging approaches indicated that embryonic DREADD activation increased calcium transients in migrating PNs and altered their migratory dynamics by increasing their pausing time. Taken together, these results support the idea that increased cell-intrinsic activity during migration acts as a stop signal for migrating cortical PNs

Transient Cell-intrinsic Activity Regulates the Migration and Laminar Positioning of Cortical Projection Neurons

Neocortical microcircuits are built during development and require the coordinated assembly of excitatory glutamatergic projection neurons (PNs) into functional networks. Neuronal migration is an essential step in this process. In addition to cell-intrinsic mechanisms, external cues including neurotransmitters regulate cortical neuron migration, suggesting that early activity could influence this process. Here, we aimed to investigate the role of cell-intrinsic activity in migrating PNs in vivo using a designer receptor exclusively activated by a designer drug (DREADD) chemogenetic approach. In utero electroporation was used to specifically express the human M3 muscarinic cholinergic Gq-coupled receptor (hM3Dq) in PNs and calcium activity, migratory dynamics, gene expression, and laminar positioning of PNs were assessed following embryonic DREADD activation. We found that transient embryonic DREADD activation induced premature branching and transcriptional changes in migrating PNs leading to a persistent laminar mispositioning of superficial layer PNs into deep cortical layers without affecting expression of layer-specific molecular identity markers. In addition, live imaging approaches indicated that embryonic DREADD activation increased calcium transients in migrating PNs and altered their migratory dynamics by increasing their pausing time. Taken together, these results support the idea that increased cell-intrinsic activity during migration acts as a stop signal for migrating cortical PNs

Happy heart syndrome: role of positive emotional stress in takotsubo syndrome

Aims Takotsubo syndrome (TTS) is typically provoked by negative stressors such as grief, anger, or fear leading to the popular term broken heart syndrome. However, the role of positive emotions triggering TTS remains unclear. The aim of the present study was to analyse the prevalence and characteristics of patients with TTS following pleasant events, which are distinct from the stressful or undesirable episodes commonly triggering TTS. Methods and results Takotsubo syndrome patients with preceding pleasant events were compared to those with negative emotional triggers from the International Takotsubo Registry. Of 1750 TTS patients, we identified a total of 485 with a definite emotional trigger. Of these, 4.1% (n = 20) presented with pleasant preceding events and 95.9% (n = 465) with unequivocal negative emotional events associated with TTS. Interestingly, clinical presentation of patients with happy heart syndrome was similar to those with the broken heart syndrome including symptoms such as chest pain [89.5% (17/19) vs. 90.2% (412/457), P = 1.0]. Similarly, electrocardiographic parameters, laboratory findings, and 1-year outcome did not differ. However, in a post hoc analysis, a disproportionate higher prevalence of midventricular involvement was noted in happy hearts compared with broken hearts (35.0 vs. 16.3%, P = 0.030). Conclusion Our data illustrate that TTS can be triggered by not only negative but also positive life events. While patient characteristics were similar between groups, the midventricular TTS type was more prevalent among the happy hearts than among the broken hearts. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTS

Clinical features and outcomes of takotsubo (stress) cardiomyopathy

METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. Full Text of Methods... RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. Full Text of Results... CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others