Use of a mouse model of anxious depression to assess the safety of pediatric anti

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DESCRIPTION (provided by applicant): This application addresses broad challenge area (15) Translational Science and specific challenge topic 15-MH-101, Effects of Psychotropic Medications on Neurodevelopment and Behavior in Animal Models". Antidepressants and anxiolytics are increasingly prescribed to pediatric patients at progressively younger ages and often for extended periods of time. These drugs act upon neurobiological substrates that undergo profound structural and functional changes from embryogenesis to childhood and adolescence, raising concerns for detrimental drug effects on brain development. In particular, treatment of children and adolescents with antidepressant drugs such as fluoxetine may result in increased suicidal behavior and lethality. Moreover, experiments in mice indicate that administration of fluoxetine during postnatal developmental stages corresponding to the last trimester of human development leads to behavior indicative of heightened anxiety and emotionality in adulthood. These effects are reminiscent of detrimental behavioral effects observed upon treatment of young mice with diazepam, a prototype benzodiazepine that potentiates the function of GABA via GABA-A receptors. Indeed, accumulating evidence suggests that antidepressants such as fluoxetine may exert their effect in part by modulation of GABAergic transmission. Fluoxetine and diazepam therefore might ultimately affect the developing nervous system through common mechanisms that call for a direct comparison. Postnatal brain development involves progressive, neural activity-dependent and function-specific maturation of GABAergic circuits, which at the cellular level includes a switch from mostly depolarizing function of GABA-A receptors to mostly hyperpolarizing effects. This developmental mechanism has been proposed to define temporal boundaries for critical periods of activity-dependent functional maturation that applies universally to most if not all brain functions. Evidence that such mechanisms might apply to the neurobiological substrate of anxiety and mood disorders is available from GABA-A receptor gamma2 subunit heterozygous mice (gamma2 mice), which have been established as an animal model of anxious depression that includes cognitive, behavioral, cellular, and endocrine characteristics associated with anxiety and mood disorders in patients. Importantly, analyses of conditional gamma2 mice suggest that the behavioral and other abnormalities in these mice are mediated by a developmental GABA-A receptor deficit. Interestingly, while diazepam administered to young mice has anxiogenic-like effects on adult behavior in wildtype (WT) mice, similar treatment of young gamma 2 mice is neutral or has anxiolytic like effects. These findings suggest that gamma2 mice exhibit GABAergic deficits in a critical period of neural plasticity in neural circuits relevant for anxiety and depressive- like behavior. Conversely, drug induced potentiation of GABAergic transmission of an otherwise normally developing brain negatively affects proper maturation of the same circuits. Given that fluoxetine and diazepam administered to young WT mice have similar anxiogenic-like effects on behavior in adulthood, we hypothesize that the two drugs interfere similarly with maturation of GABAergic circuits that are relevant for anxiety and depression-related behavior. To further address the mechanism of potentially detrimental developmental effects of fluoxetine and diazepam we here propose to i) determine and compare the postnatal developmental windows during which these two drugs affect behavior of WT and GABAAR gamma2 subunit heterozygous mice in adulthood. In addition, we will analyze and compare the developmental effects of these drugs on diverse molecular and cellular markers that are altered in gamma 2 mice and are implicated in anxiety and depression-related behavior. These studies will alert to potentially detrimental effects of antidepressant and anxiolytic drug on the developing postnatal brain and will help to delineate detrimental from neutral or possibly beneficial drug effects on brain development. In addition, they may advance the design and safety of antidepressant and anxiolytic therapies directed specifically at pediatric and adolescent patients. PUBLIC HEALTH RELEVANCE: Antidepressants, anxiolytics and other psychotropic medications are increasingly prescribed to pediatric patients at progressively younger age and often for extended periods of time. These drugs act upon neurobiological substrates that undergo profound structural and functional changes during childhood and adolescence, yet their mechanisms of action in the developing nervous system are largely unknown. We here take advantage of a mouse model of anxious depression to assess molecular, cellular, endocrine and behavioral consequences of antidepressant drug treatment in young animals representative of pedriatic patients. These studies will alert to potentially detrimental effects of antidepressant and anxiolytic drug on the developing postnatal brain and will help to delineate detrimental from neutral or possibly beneficial drug effects on brain development. In addition, they may advance the design and safety of antidepressant and anxiolytic therapies directed specifically at pediatric and adolescent patients.