Functional Implication of Alpha2C Adrenoceptors in Limbic System Using Adra2c Knock-out / lacZ Knock-in Mice

• Main Authors: Hui-Chu Lin, 林蕙竹
• Other Authors: Alice Chien Chang
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/57798534568484144257

碩士 === 國立陽明大學 === 神經科學研究所 === 97 === In the central nervous system (CNS), the majority of norepinephrine (NE) neurons are located in the locus coeruleus. The NE axon fibers project to extensive areas of the brain including cerebral cortex, hippocampus, thalamus, brain stem, cerebellum and spinal cord. The NE neurotransmission system has been implicated in cognitive and affective functions and disturbed NE neurotransmission is known to result in psychiatry disorders. α2- adrenoceptors (α2-ARs) are one of the G-protein-coupled receptor (GPCR) classes mediating the effects of NE. They are further classified into 3 subtypes; α2A-, α2B- and α2C-ARs. Using Adra2c-knockout/lacZ- knockin (KO-KI) mice, we can map directly the expression pattern of α2C-AR in the CNS, and also investigate its function in these areas. One of the major brain regions with significant α2C-AR expression is hippocampus, known to be key to learning and memory. We have previously demonstrated that the Adra2c-KO/lacZ-KI mice have a higher tendency of aggression than the wildtype (WT) control (C57BL/6). The present study was aimed to delineate the functional role of α2C-AR in emotional memory in this area. A modified Residenet-Intruder paradigm (RI) was used as a test of aggression and its associated emotional memory. The hippocampal LTP of KO mice post-RI not only was significantly higher than group housing or isolated KO-KI mice, it may also be higher than that of the WT after the behavioral test. But the LTP of WT mice after behavioral test was not different from its group housing or isolated counterparts. We suggest that a2C-AR is involved in the induction and maintenance of LTP elicited by this particular type of emotional memory. The deficiency of α2C-AR in the CA1 pyramidal neurons of both dorsal and ventral hippocampus might significantly affect the NE transmission and its intricate networking with the serotonin and dopamine systems in the CNS. Using immunohistochamistry (IHC) and Western blot, we have found in the α2C-AR-deficient mice: (i) the expression level of NR1 in dorsal hippocampus is lower than that of the WT, (ii) the expression level of calbindin-D28K was decreased in dorsal hippocampal CA1 pyramidal cells, where α2C-AR expression is abundant in WT. It is possible that these changes may be the cause of the unsustainable LTP in the α2C-AR deficient mice. Moreover, the decreased level of BDNF found in lateral septum of the α2C-AR deficient mice suggest that the catecholamine (NE and DA) projections into this area may be decreased which led to the decrease of calbindin-D28K in the GABAergic spiny interneurons. Since most messages between different areas of the limbic system are processed through and modulated by septum, so the abnormality in the lateral septum may affect the regulation of neurotransmission between other limbic system areas. In conclusion, the present studies provide evidence that α2C-AR might take part in the regulation of excitability of hippocampal neurons. Because the balance between different systems in the brain may not be the same before and after behavioral task, while lacking α2C-AR cause the imbalance between different modulatory systems, so the LTP elicited from different behavioral experiences was abnormal under the condition of α2C-AR deficiency.