13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

Abstract

The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg͞kg͞day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.A ccutane, the active component of which is 13-cis-retinoic acid (RA), is the primary treatment for chronic acne. RA induces differentiation and reduces proliferation of stem and progenitor cells, and 13-cis-RA helps control acne by inducing similar events in basal sebocytes (1). These same actions also lead to 13-cis-RA's side effects, and these are directed toward proliferating cells in the adult such as in the skin, gut, and bone (2). However, Accutane has also been reported to modify behavior, sometimes resulting in severe depression with suicidal ideation (2-4). It is surprising that 13-cis-RA might influence the adult brain, an organ in which there is not extensive proliferation. Certainly, this effect has been considered contentious (5), in large part because no mechanism has been described for such an etiology. Cell proliferation, however, is known to occur in restricted regions of the adult brain. New neurons are born and develop in the subgranular zone (SGZ) of the hippocampal formation as well as in the subventricular zone (SVZ) of the forebrain and in its extension via the rostral migratory stream to the olfactory bulb (6). If 13-cis-RA influences the brain, then these proliferating cells would be likely targets. We show, in a mouse model, that 13-cis-RA, at a dose of 1 mg͞kg͞day, reduces both the rate of hippocampal cell birth and the number of newborn neurons. Because the hippocampus is primarily associated with memory processing, and new neuronal birth has been suggested to be required for this task (7), it would also be predicted that 13-cis-RA would result in a decline in hippocampal-dependent memory. In this study, we demonstrate that, by using a radial arm maze test, there is a severe defect in the ability of 13-cis-RA-injected mice to perform this task, suggesting that long-term exposure to 13-cis-RA can disrupt hippocampaldependent behavior. MethodsBrdUrd Treatment. Mice were injected with BrdUrd in two types of experimental paradigms, the first to determine the influence of RA on the rate of cell proliferation in the hippocampus and the second as a cell marker to follow cell survival. To follow cell proliferation (Fig. 1A), RA was injected dail...

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

“…However, our present findings indicated that normal hippocampal function requires precise adjustment of retinoid-mediated transcription control, and vitamin A nutritional intake is one factor involved in this regulation. Although retinoid signaling hypoexpression could account for aging-related hippocampal dysfunction (Brouillette and Quirion, 2007), vitamin A or RA in excess during adulthood might have disruptive effects (Crandall et al, 2004).…”

“…Functional implication of retinoid signaling in hippocampal plasticity and spatial memory was demonstrated in rodents by knock-out of RAR␤ or RXR␤/␥ receptors (Chiang et al, 1998;Wietrzych et al, 2005), vitamin A deprivation (Misner et al, 2001;Cocco et al, 2002;Etchamendy et al, 2003b), and RA administration (Crandall et al, 2004). Furthermore, dysfunction of retinoid signaling pathway has been hypothesized to be involved in human neurodevelopmental pathologies such as schizophrenia or late-onset Alzheimer's disease (for review, Goodman, 1998Goodman, , 2006Goodman and Pardee, 2003;Palha and Goodman, 2006).…”

Administração prolongada do ácido 13-cis-retinóico (isotretinoína) em camundongos machos adolescentes: comportamentos emocionais e quantificação de transcritos de componentes do sistema serotoninérgico central.

“…Estudos evidenciaram que tanto a carência quanto o excesso de suprimento de retinóides são prejudiciais na fase embriogênica e adulta, demonstrando a importância de se ter um suprimento adequado de retinol (Bonnet et al, 2008;Crandall et al, 2004;Lammer et al, 1985;Maden et al, 1996). No embrião, o ácido retinóico (RA) é imprescindível na morfogênese, atuando no padrão de desenvolvimento anteroposterior, dorsoventral e na formação do tubo neural (Maden et al, 1996).…”

“…Neste sentido, um estudo envolvendo administração crônica do 13-cis-RA em camundongos verificou uma redução na taxa de proliferação e neurogênese no hipocampo de camundongos (Crandall et al, 2004). O hipocampo é uma das poucas áreas encefálicas onde ainda ocorre proliferação de neurônios no cérebro maduro (Eriksson et al, 1998).…”

“…Os retinóides apresentam capacidade de modular alterações na sinapse como LTP (long term potentiation) e LTD (long term depression), e devido sua atividade na diferenciação celular, é capaz de regular o processo de neurogênese (Bonnet et al, 2008;Crandall et al, 2004;Misner et al, 2001).…”