SAM-resistant 1 Research Articles

Deterioration in synaptic plasticity of cultured hippocampal neurons of senescence-accelerated mouse prone8

Senescence-accelerated mouse (SAM) have been used as animal models in the studies of senescence and age-associated disorders for many years. The typical feature of SAM-prone8 (SAMP8), a substrain of SAM, is the development of early onset of learning and memory deficit during its aging process, while SAM-resistant1 (SAMR1) shows normal aging process. To study the synaptic mechanism underlying the cognitive deterioration of SAMP8, whole-cell recording technique was used to compare the synaptic function of cultured SAMP8 hippocampal neurons with that of SAMR1 in our experiments. Paired-pulse depression (PPD), a simple form of use-dependent synaptic plasticity, is measured in autapse in response to paired stimulation. Those autapses in tests possessed the compatible evoked EPSC in amplitude. However, the degree of PPD in cultured hippocampal neurons of SAMP8 was far larger and the time constant of the autapse recovery from PPD was longer than those of SAMR1. In addition, mEPSC recorded in autapse were lower in frequency in SAMP8 compared with that of SAMR1, but with the similar amplitude, suggesting that presynaptic mechanism was involved. These results suggested that the synaptic plasticity of hippocampal neurons of SAMP8 is deficient compared to that of SAMR1, which may be caused by some kind of presynaptic functional disorders.

Functional relationship between age-related immunodeficiency and learning deterioration.

Disordered immune responses are supposed to alter the function of the central nervous system through the neuroendocrine immunomodulation network. In this paper, we studied the influence of the immune function on learning performances from the angle of pharmacology using aged garlic extract (AGE), an immunomodulator. Splenocyte proliferation, induced by concanavalin A or lipopolysaccharide, and the antibody production response were declined in senescence accelerated mouse-prone 8 (SAMP8) aged 12 months compared with age-matched SAMR1 (SAM-resistant 1). Chronic oral administration of AGE-containing food (2%, w/w) significantly enhanced the immune responses of both SAMP8 and SAMR1. Male ddY mice were thymectomized 4 weeks after birth and fed AGE-containing food after the operation until the experiments were finished. Learning performances, brain monoamine content and choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated 10 months after the operation. Thymectomy resulted in not only immunodeficiency, but also deteriorated learning ability. AGE treatment prevented the reduction of the antibody production response induced by thymectomy and improved the thymectomy-induced deterioration of learning behaviours in passive avoidance performance and in a spatial memory task. The contents of hypothalamic noradrenaline, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the hypothalamic ChAT activity were increased in thymectomized mice compared to those of sham-operated control, while AGE treatment restored them to the control levels. These results suggest that the improvement of immune function is closely related to the amelioration of age-associated deterioration of learning and memory.

Sphingomyelinase Activity Is Enhanced in Cerebral Cortex of Senescence-Accelerated Mouse-P/10 with Advancing Age

The cerebral cortical sphingomyelinase (SMase) activities were detected in the cytosolic and the membrane fractions of cerebral cortex, hippocampus, cerebellum, brainstem, and thalamus/midbrain of senescence-accelerated mouse-prone/10 (SAM-P/10) and SAM-resistant/1 (SAM-R/1) with advancing age, respectively. The SMase activity was increased uniquely in the membrane fraction of the cerebral cortex of SAM-P/10 in an age-dependent manner; The enzyme activities of 10 and 17 months of age were about 25 and 30% higher than those of 2 months of age, respectively. This observation implicates that the membrane-associated SMase activity might be related with accelerated senescence. The cerebral cortical SMase was eluted in a molecular mass of approximately 400 kDa on a gel filtration chromatography and was active in a broad range of pH from 4 to 9. It was also suggested that phosphorylation may be one of the mechanisms regulating the enzyme activity, but not responsible for the increased activity with advancing age.