Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Abstract

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a populationspecific serotonin 2B (5-HT 2B ) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT 2B mutant (Htr 2B − / − ) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT 2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT 2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr 2B − / − mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr 2B − / − mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT 2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophreniclike phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT 2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT 2B receptors in the neurobiology of psychotic disorders.

Differential control of dopamine ascending pathways by serotonin2B receptor antagonists: New opportunities for the treatment of schizophrenia

“…This result, together with the finding that 5-HT 2B R blockade inhibits haloperidol-induced DA outflow in the NAc but not in the striatum (Auclair et al, 2010), suggests that it may be possible to generate a clozapine-like neurochemical profile when combining 5-HT 2B R and DA-D 2 R antagonisms, as previously observed with other 5-HT receptors, such as the 5-HT 2A R (Ichikawa and Meltzer, 2000;Meltzer et al, 2003). Furthermore, that 5-HT 2B Rs could play a role in the neurobiology of schizophrenia has been recently suggested by a study performed in the constitutive 5-HT 2B R knock-out mice (Pitychoutis et al, 2015). At variance with the present findings, this study concluded that the genetic ablation of the 5-HT 2B R leads to a schizophrenic-like phenotype.…”

“…In agreement with the role of 5-HT 2B Rs in brain maturation (Kolodziejczak et al, 2015), it is conceivable that the observed phenotype could result from profound neural adaptations triggered by the permanent lack of this receptor. However, the fact that acute pharmacological blockade of 5-HT 2B Rs phenocopied some behavioral responses observed in knock-out mice (Pitychoutis et al, 2015), points out that additional factors, such as the use of different species, may account for the different conclusion offered by the present study. Future investigations in animals chronically treated with 5-HT 2B R antagonists as well as in advanced genetic models, such as conditional 5-HT 2B R knock-out animals, are warranted to address this issue.…”

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Indeed, Htr2b -/-mice were recently shown to display deficits in social interactions, as well as in learning and memory processes [54], and these processes require intact frontal lobe function. Along the same lines, the Q20* polymorphism, only found in the Finnish population, is associated with severe impulsivity [3], possibly caused by frontal lobe modulation.…”

A quantitative trait locus on chromosome 1 modulates intermale aggression in mice

“…Htr2b −/− mice are hyperactive and have deficits in pre-pulse inhibition of the startle response, social interaction, memory, and attention, and increases in wakefulness as well as impulsivity (Pitychoutis et al , 2015). …”

“…Htr2b −/− mice are hyperactive and have deficits in pre-pulse inhibition of the startle response, social interaction, memory and attention, and increases in wakefulness as well as impulsivity. 37 HTR2B mutations are also associated with aggression in other species, such as pigs 38 and zebrafish. 39 In humans, a specific 5-HT2B receptor stop codon (HTR2B Q20*) observed in a Finnish male population segregates with severe impulsivity, psychosis and early-onset schizophrenia.…”