Disruption of sphingomyelin synthase 2 gene alleviates cognitive impairment in a mouse model of Alzheimer's disease.

The membrane raft accommodates the key enzymes synthesizing amyloid ß (Aß). One of the two characteristic components of the membrane raft, cholesterol, is well known to promote the key enzymes that produce amyloid-ß (Aß) and exacerbate Alzheimer's disease (AD) pathogenesis. Given that the raft is a physicochemical platform for the sound functioning of embedded bioactive proteins, the other major lipid component sphingomyelin may also be involved in AD. Here we knocked out the sphingomyelin synthase 2 gene (SMS2) in 3xTg AD model mice by hybridization, yielding SMS2KO mice (4S mice). The novel object recognition test in 9/10-month-old 4S mice showed that cognitive impairment in 3xTg mice was alleviated by SMS2KO, though performance in the Morris water maze (MWM) was not improved. The tail suspension test detected a depressive trait in 4S mice, which may have hindered the manifestation of performance in the wet, stressful environment of MWM. In the hippocampal CA1, hyperexcitability in 3xTg was also found alleviated by SMS2KO. In the hippocampal dentate gyrus of 4S mice, the number of neurons positive with intracellular Aß or its precursor proteins, the hallmark of young 3xTg mice, is reduced to one-third, suggesting an SMS2KO-led suppression of syntheses of those peptides in the dentate gyrus. Although we previously reported that large-conductance calcium-activated potassium (BK) channels are suppressed in 3xTg mice and their recovery relates to cognitive amelioration, no changes occurred by hybridization. Sphingomyelin in the membrane raft may serve as a novel target for AD drugs.

Spatiotemporal development of the neuronal accumulation of amyloid precursor protein and the amyloid plaque formation in the brain of 3xTg-AD mice.

The amyloid plaque is a hallmark of Alzheimer's disease. The accumulation of the amyloid precursor protein (APP) in the neuronal structure is assumed to lead to amyloid plaque formation through the excessive production of ß-amyloid protein. To study the relationship between the neuronal accumulation of APP and amyloid plaque formation, we histologically analyzed their development in the different brain regions in 3xTg-AD mice, which express Swedish mutated APP (APPSWE) in the neurons. Observation throughout the brain revealed APPSWE-positive somata in the broad regions. Quantitative model analysis showed that the somatic accumulation of APPSWE developed firstly in the hippocampus from a very early age (<1 month) and proceeded slower in the isocortex. In line with this, the hippocampus was the first region to form amyloid plaques at the age of 9-12 months, while amyloid plaques were rarely observed in the isocortex. Females had more APPSWE-positive somata and plaques than males. Furthermore, amyloid plaques were observed in the lateral septum and pontine grey, which did not contain APPSWE-positive somata but only the APPSWE-positive fibers. These results suggested that neuronal accumulation of APPSWE, both in somatodendritic and axonal domains, is closely related to the formation of amyloid plaques.

Vocalization during agonistic encounter in Mongolian gerbils: Impact of sexual experience.

Behaviors and vocalizations associated with aggression are essential for animals to survive, reproduce, and organize social hierarchy. Mongolian gerbils (Meriones unguiculatus) are highly aggressive and frequently emit calls. We took advantage of these features to study the relationship between vocalizations and aggressive behaviors in virgin and sexually experienced male and female Mongolian gerbils through the same-sex resident-intruder test. Both sexes of resident gerbils exhibited aggressive responses toward intruders. Multiparous females exhibited the most aggressive responses among the four groups. We also confirmed two groups of vocalizations during the encounters: high-frequency (>24.6 kHz) and low-frequency (<24.6 kHz). At the timing of high-frequency vocalizations observed during the tests, the vast majority (96.2%) of the behavioral interactions were non-agonistic. While, at the timing of low-frequency vocalizations observed during the tests, around half (45%) of the behavioral interactions were agonistic. Low-frequency vocalizations were observed mainly during encounters in which multiparous females were involved. These results suggest that high- and low-frequency vocalizations relate to non-agonistic and agonistic interactions, respectively. In addition to affecting aggressive behavior, sexual experience also affects vocalization during encounters. These findings provide new insights into the modulatory effects of sex and sexual experience on vocalizations during agonistic encounters.

Remodeling of projections from ventral hippocampus to prefrontal cortex in Alzheimer's mice.

Emotional dysregulation often accompanies cognitive deficits in Alzheimer's disease (AD). The hippocampus, most notably damaged by AD pathology, is classified into the cognition-bound posterior and emotion-bound anterior hippocampi. Since the anterior hippocampus or its rodent counterpart, the ventral hippocampus (VH), sends dense afferents to the prefrontal cortex (PFC) and the basolateral amygdala (BLA), the two structures implicated in fear responses, we investigated whether these afferents are modified in 3xTg AD model mice. An anterograde dextrin tracer injected into VH revealed that axons in PFC were more ramified in 3xTg than wild-type (WT) mice, with the synaptic density reduced. The VH projections to BLA were not affected. Intracellular accumulation of amyloid ß (Aß) or Aß-like immunoreactivity was found in PFC and BLA neurons alike. Behaviorally, in the 2-way active avoidance test, the frequency of chamber change was higher, with the test performance better, in 3xTg than WT mice, suggesting a distorted contextual fear in the 3xTg group. Given the essential involvement of parts of PFC in contextual fear responses and that of BLA in fear responses in general, the observed remodeling of VH-to-PFC afferents and the accumulation of intracellular Aß in BLA and PFC pyramidal cells might exercise critical influences on enhanced avoidance behavior in 3xTg mice.