The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.
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-HT 2C 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-HT 2C 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-HT 2C premRNA editing phenotype remained unaltered. Hence, the similar behavioral effects of enrichment and fluoxetine treatment during adolescence were not accompanied by similar changes in 5-HT 2C 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␣q subunit of G-protein that couples to 5-HT 2A/2C receptors. In contrast, G␣q expression levels were significantly lower in fluoxetine-treated mice. These findings suggest that compensatory changes in G␣q expression occur in mice with persistently altered 5-HT 2C pre-mRNA editing and provide an explanation for the dissociation between 5-HT 2C receptor editing phenotypes and behavioral stress responses.
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 CREBtransduced 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 agingrelated 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.adeno-associated virus vector ͉ inducible cAMP early repressor ͉ long-term memory ͉ hippocampus D eficits in hippocampus-dependent long-term memory, which accompany normal aging, have been reported for many mammal species, including rats (1, 2), mice (3), monkeys (4), and humans (5). However, molecular mechanisms underlying such age-related changes are still unknown.Studies by Kandel and colleagues (6) using in vitro cultures of mollusk neurons revealed the involvement of the transcription factor cAMP response element-binding protein (CREB) in the molecular mechanisms underlying long-term facilitation. Further behavioral analysis in Drosophila (7, 8) and mice (9, 10) demonstrated that CREB is necessary for long-term-memory formation both in nonmammalian and mammalian species. Also, pharmacological antagonism and genetic disruption of CREB signaling prevents or attenuates long-term-memory consolidation in these model systems.CREB is constitutively expressed in cells, with the phosphorylation of Ser-133 generally believed to be the main mechanism of regulation of its transcriptional activity (11). However, several studies indicate that the CREB protein concentration might be critical in some aspects of long-term-memory formation. A transgenic fly that overexpresses an active form of CREB shows a lower threshold for the consolidation of long-term memory (8). Also, transiently increasing WT CREB levels in the basolateral amygdala by means of herpes simplex virus vector-mediated gene transfer facilitates long-term-memory formation after massed fear training (12).There is no direct evidence that implicates CREB in agerelated memory impairment. However, electrophysiological stud...
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.
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