ABSTRACT
Infant maternal separation, a paradigm of early life stress in rodents, elicits long-lasting changes in gene expression that persist into adulthood. In BALB/c mice, an inbred strain with spontaneously elevated anxiety and stress reactivity, infant maternal separation led to increased depression-like behavioral responses to adult stress and robustly increased editing of serotonin 2C receptor pre-mRNA. Chronic fluoxetine treatment of adult BALB/c mice exposed to early life stress affected neither their behavioral responses to stress nor their basal 5-HT2C pre-mRNA editing phenotype. However, when fluoxetine was administered during adolescence, depression-like behavioral responses to stress were significantly diminished in these mice, and their basal and stress-induced 5-HT2C pre-mRNA editing phenotypes were significantly lower. Moreover, when BALB/c mice exposed to early life stress were raised in an enriched postweaning environment, their depression-like behavioral responses to adult stress were also significantly diminished. However, their 5-HT2C pre-mRNA editing phenotype remained unaltered. Hence, the similar behavioral effects of enrichment and fluoxetine treatment during adolescence were not accompanied by similar changes in 5-HT2C pre-mRNA editing. Enriched and nonenriched BALB/c mice exposed to early life stress also exhibited significantly increased expression of mRNA and protein encoding the G alpha q subunit of G-protein that couples to 5-HT2A/2C receptors. In contrast, G alpha q expression levels were significantly lower in fluoxetine-treated mice. These findings suggest that compensatory changes in G alpha q expression occur in mice with persistently altered 5-HT2C pre-mRNA editing and provide an explanation for the dissociation between 5-HT2C receptor editing phenotypes and behavioral stress responses.
Subject(s)
Anxiety, Separation/genetics , Depressive Disorder/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Mice, Inbred BALB C/physiology , RNA Editing , RNA Precursors/genetics , Receptor, Serotonin, 5-HT2C/genetics , Serotonin/physiology , Age Factors , Animals , Anxiety, Separation/complications , Anxiety, Separation/psychology , Body Weight , Depressive Disorder/drug therapy , Depressive Disorder/etiology , Depressive Disorder/physiopathology , Depressive Disorder/psychology , Emotions , Environment , Female , Fluoxetine/pharmacology , Fluoxetine/therapeutic use , GTP-Binding Protein alpha Subunits, Gq-G11/biosynthesis , Genetic Predisposition to Disease , Helplessness, Learned , Male , Mice , Mice, Inbred BALB C/genetics , Mice, Inbred BALB C/psychology , Mice, Inbred C57BL , Neocortex/metabolism , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Protein Isoforms/physiology , Random Allocation , Receptor, Serotonin, 5-HT2C/biosynthesis , Receptor, Serotonin, 5-HT2C/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Species Specificity , SwimmingABSTRACT
cAMP response element-binding protein (CREB) is important for the formation and facilitation of long-term memory in diverse models. However, to our knowledge, involvement of CREB in age-associated memory impairment has not been reported. Here, we use a recombinant adeno-associated virus vector to obtain stable transgenic expression of CREB as well as the inducible cAMP early repressor (ICER) in the hippocampus of adult rats. In a longitudinal study, we show that somatic gene transfer of both CREB and ICER does not alter long-term memory in young (3-month-old) rats. However, at 15 months of age, the same CREB-transduced rats show significantly better long-term memory in spatial-navigation and passive-avoidance tasks compared with their equally aged control littermates, and a threshold effect is evident. In contrast, the aged ICER-transduced rats demonstrate significantly reduced memory in comparison with the same control group. Hippocampal CREB gene transfer prevented the aging-related decrease in long-term memory found in the control rats. These data suggest that elevation of CREB protein levels in a subset of hippocampal neurons as achieved by somatic cell gene transfer might compensate for general deficits in molecular mechanisms underlying age-related memory loss in rats and, therefore, attenuate long-term-memory impairment during normal aging.
Subject(s)
Aging/genetics , Behavior, Animal , Cyclic AMP Response Element-Binding Protein/genetics , Genetic Therapy , Memory Disorders/therapy , Adenoviridae/genetics , Animals , Cells, Cultured , Cyclic AMP Response Element-Binding Protein/analysis , Hippocampus/chemistry , Hippocampus/metabolism , Humans , Male , Memory Disorders/genetics , RNA, Messenger/analysis , RNA, Messenger/metabolism , Rats , Rats, Wistar , Transduction, Genetic , TransgenesABSTRACT
Homer proteins mediate molecular rearrangements leading to changes in spine morphology. This points to a role of Homer in learning and memory. Homer 1c features both the ligand binding domain and a coiled-coiled domain for self-multimerization. Homer 1a lacks the coiled-coiled domain. Here, we report a new isoform which we termed 1g, lacking the Homer ligand binding domain. We dissected the functional roles of the individual Homer 1 domains, encoded by Homer 1a, 1c, and 1g, in vivo. Recombinant adeno-associated virus (AAV)-mediated overexpression of these forms in the hippocampus of adult rats has opposing effects on learning behavior. Increased levels of Homer 1a impaired hippocampal-dependent memory, while Homer 1g and 1c slightly enhanced memory performance. Homer 1g induced anxiety. Moreover, AAV-Homer 1a animals showed attenuation of electrographic seizures in a model of status epilepticus. These results suggest that Homer 1 proteins play an active role in behavioral plasticity.
Subject(s)
Carrier Proteins/metabolism , Epilepsy/metabolism , Genetic Predisposition to Disease/genetics , Hippocampus/metabolism , Memory Disorders/metabolism , Animals , Anxiety Disorders/genetics , Anxiety Disorders/metabolism , Carrier Proteins/genetics , Carrier Proteins/isolation & purification , Cell Line , Cognition/physiology , Dependovirus/genetics , Disease Models, Animal , Epilepsy/genetics , Gene Expression/physiology , Genetic Vectors/genetics , Hippocampus/physiopathology , Homer Scaffolding Proteins , Humans , Male , Memory/physiology , Memory Disorders/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary/genetics , Protein Structure, Tertiary/physiology , Rats , Rats, Wistar , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolismABSTRACT
Memory is the process by which organisms are able to record their experiences, and use this information to adapt their responses to the environment. As such, it is vital for survival. In recent years, the development of spatially and temporally selective techniques for the regulation of gene expression has allowed the molecular details of this process to emerge. Here we review the molecular mechanisms thought to underlie memory acquisition and storage, as well as discuss recent evidence regarding the mechanisms of subsequent memory consolidation.