Transgenic mouse model for the formation of Hirano bodies

Abstract

BackgroundHirano bodies are actin-rich cytoplasmic inclusions found predominantly in the brain in association with a variety of conditions including aging and Alzheimer's disease. The function of Hirano bodies in normal aging and in progression of disease has not been extensively investigated due to a lack of experimental model systems. We have developed a transgenic mouse model by expression of a gain-of-function actin cross-linking protein mutant.ResultsWe used the Cre/loxP system to permit tissue specific expression of Hirano bodies, and employed the murine Thy 1 promoter to drive expression of Cre recombinase in the brain. Hirano bodies were observed in the cerebral cortex and hippocampus of homozygous double transgenic 6 month old mice containing Cre. The Hirano bodies were eosinophilic rods, and also exhibited the paracrystalline F-actin filament organization that is characteristic of these inclusions. Mice with Hirano bodies appear healthy and fertile, but exhibited some alterations in both short-term and long-term synaptic plasticity, including paired-pulse depression rather than facilitation, and decreased magnitude of early LTP.ConclusionsHirano bodies are not lethal and appear to have little or no effect on histology and tissue organization. Hirano bodies do modulate synaptic plasticity and exert clearly discernable effects on LTP and paired-pulse paradigms. This model system will allow us to investigate the impact of Hirano bodies in vivo, the pathways for formation and degradation of Hirano bodies, and whether Hirano bodies promote or modulate development of pathology and disease progression.

Hirano body expression impairs spatial working memory in a novel mouse model

“…Interestingly, despite the important role of actin in LTP, we found that there was no measurable difference between R26CT and R26CT-CRE mice at either 3 or 8 months of age (Figure 10) in the ventral hippocampus. These results are in contrast with those observed in our earlier study in which R26CT x Thy1.2-CRE mice showed a deficit in the early, but not the late phase LTP [28]. Thus, presence of model Hirano bodies in the CA1 region of the ventral hippocampus of R26CT-CRE mice (current R26CT × CamKIIa-CRE mouse) appears to have negligible effects on synaptic plasticity as assessed by pairedpulse and LTP measurements.…”

“…Thus, presence of model Hirano bodies in the CA1 region of the ventral hippocampus of R26CT-CRE mice (current R26CT × CamKIIa-CRE mouse) appears to have negligible effects on synaptic plasticity as assessed by pairedpulse and LTP measurements. Once again, the presynaptic expression of model Hirano bodies in the CA3 of the Thy1.2-CRE mouse resulted in significant effects in the former report [28] that were not observed with the postsynaptic expression pattern in the CA1 of the current CAMKIIa-CRE mouse.…”

“…Taken together, the effects of expression of model Hirano bodies in the presynaptic CA3 of R26CT x Thy1.2-CRE mouse [28] were readily discernable compared to the postsynaptic expression in the CA1 of the current R26 x CamKIIa-CRE mouse. 8 month old R26CT-CRE mice have an impairment in spatial working memory assessed utilizing the spatial win-shift task in the radial arm maze despite no significant differences in either short-term or long-term plasticity measurements in the ventral hippocampus that could readily explain this cognitive deficit [90,91].…”

“…The most obvious explanation for this is due to differences in the expression pattern of CT-GFP between the two mouse strains. In the current study, CT-GFP expression and Hirano body formation was more predominant in the CA1 subregion of the hippocampus versus the previous mouse model that had predominantly CA3 subregion expression and subsequent Hirano body formation [28][29][30]. In both cases, field potential recordings were performed in the stratum radiatum layer of CA1 by activating the Schaffer collateral axons (which originate in CA3) and synapse on the apical dendrites of the CA1 pyramidal neurons.…”

“…In both cases, field potential recordings were performed in the stratum radiatum layer of CA1 by activating the Schaffer collateral axons (which originate in CA3) and synapse on the apical dendrites of the CA1 pyramidal neurons. In the previous mouse (R26CT x Thy1.2-CRE), Hirano bodies were formed in presynaptic CA3 neurons [28]. Pairedpulse stimulation is a measurement that reflects the active transport recovery of calcium and trafficking of neurotransmitter-containing vesicles to replenish the ready releasable pool of vesicles [74].…”