Modeling early cortical serotonergic deficits in autism

Abstract

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro-and macroscopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

Schizophrenia seen as a deficit in the modulation of cortical minicolumns by monoaminergic systems

“…Ablation of mesocortical dopamine projections results in pathological deficits similar to those reported in schizophrenia, including; reductions in cortical width (Onteniente, Konig, & Sievers, 1980), decreased dendritic branching (Kalsbeek et al, 1987), and layer specific reduction in dendritic length and spine density (Felten, Hallman, & Jonsson, Felten 1982). Similarly, selective serotonin depletion of the cortex results in changes in cortical width (Boylan, Blue, & Hohmann, 2007). It is therefore of interest that the ontogeny of the monoaminergic system exhibit sex and hemisphere specific differences analogous to those reported in schizophrenia (Connell, Karifari, & Hohmann, 2004).…”

Serotonin: a regulator of neuronal morphology and circuitry

“…Both result in animals with reduced serotonergic function either due to developmental downregulation of the serotonergic system or early serotonin toxin administration [71–73]. In both cases, animals exhibit decreased serotonergic terminals in the brain, decreased responsiveness to auditory stimuli, decreased behavioral inhibition, altered social interactions, and cortical defects including metabolic abnormalities that the authors interpret as consistent with autism [72,73]. While it is difficult to model all aspects of a complex human condition like autism in experimental systems, these studies do demonstrate the critical nature of appropriate serotonin levels during brain development and potential consequences of dysfunction.…”

Advances in behavioral genetics: mouse models of autism

“…176 As adults, mice with neonatal loss of serotonergic neurons demonstrate impaired social learning, increased repetitive digging and grooming behaviors, and increased social aggression. 177 The consequences of other alterations in 5-HT signaling can be seen in the phenotypes of mouse lines bearing targeted disruptions in the pathway. [42][43][44]178,179 Many of the genes involved in 5-HT signaling have been mutated in the mouse, including receptors, metabolic and catabolic enzymes, SERT, and others.…”