This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- MH-101: Effect of psychotropic medications on neurodevelopment and behavior in animal models. Selective serotonin reuptake inhibitors (SSRIs) have become the mainstream therapy in psychiatric diseases. Based on their therapeutic effect in adults, they are increasingly prescribed in children and adolescents. However, there is a concern about the use of SSRIs in young patients, in particular, due to reports of increased susceptibility to suicide. Recently, in mouse models, chronic SSRI administration at an early postnatal time frame, corresponding to 3rd trimester to childhood has been shown to lead to increased anxiety in adulthood, suggesting that SSRI treatment in young mice is anxiogenic. This suggests that the developing brain responds to SSRIs very differently than the adult brain. However, rigorous examination of the effects of SSRIs on more clinically relevant postnatal time frames, encompassing late childhood through adolescence, have not been performed in these model systems. One important mechanism by which SSRIs may attenuate anxiety in adulthood is through the induction of BDNF levels in critical brain regions, such as the hippocampus, prefrontal cortex, and mesolimbic reward circuit. Although BDNF levels are stable in adults, in early postnatal life, BDNF expression is peaking and is dynamically regulated presumably due to its critical role in neural circuit maturation. BDNF exists in 2 isoforms, an initially synthesized precursor, proBDNF, and a smaller mature BDNF form. Expression of proBDNF is highest in early postnatal life, whereas mature BDNF predominates in adults. Recent studies suggest that proBDNF and mature BDNF may play divergent roles in synaptic maturation and plasticity. ProBDNF released from presynaptic sites binds to p75 to induce long term depression (LTD), and to potentially reduce spine density and dendritic complexity, whereas mature BDNF promotes long term potentiation (LTP) and enhanced dendritic morphology. We hypothesize that induction of BDNF by SSRIs in childhood and adolescence may lead to altered neuronal morphology and function, and abnormal circuitry between cortex, hippocampus, and nucleus accumbens. These studies, utilizing new technical advances in BDNF detection will allow us to determine how SSRIs, delivered during vulnerable periods during childhood and adolescence (a) perturbs BDNF levels, BDNF isoform conversion, and signaling through BDNF receptors acutely, and in adulthood;(b) induce adult anxiety and depressive phenotypes. We predict that the postnatal developmental changes in proBDNF and mature BDNF ratios may underlie critical differential effects of SSRI antidepressants on modulating structural and functional neural plasticity, leading to long-lasting abnormal behavioral responses in animals treated with SSRIs during critical childhood periods of vulnerability.
Based on their therapeutic effect in adults, selective serotonin reuptake inhibitors (SSRIs) are increasingly being prescribed in children and adolescents. However, there is a concern about the longterm consequences of these medications. Importantly, several animal model studies have shown that early life SSRIs can have deleterious behavioral effects later in life such as abnormal anxiety-related behaviors, as well as responses to stress. Our studies, utilizing new technical advances in detection of the growth factor, BDNF, in mouse models will allow us to determine how SSRIs, delivered during vulnerable periods during childhood and adolescence, affects regulation of this critical growth factor to modulate structural and functional neural plasticity, leading to long-lasting abnormal behavioral responses to SSRIs during critical childhood periods of vulnerability.
