Electrophysiological Characterization of Hippocampus in α2C Adrenoceptor Null Mice

• Main Authors: Yung-Jen Kung, 龔雍任
• Other Authors: Alice Chien Chang
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/03007772424870638910

碩士 === 國立陽明大學 === 神經科學研究所 === 93 === Norepinephrine (NE) projection from locus coeruleus to hippocampus has been established for long yet how it modulates the function of hippocampus has not been fully elucidated. α2 Adrenoceptor (AR), a class of NE receptor, mediates many physiological responses of NE and belongs to G protein-coupled receptor gene family. Expression of mouse α2C adrenoceptor (α2C-AR), one of the three α2 adrenoceptor subtypes, encoded by Adra2c, has been mapped to CA1 of hippocampus by in situ X-gal staining in Adra2c-KO/lacZ-KI mutant mice established in our lab. Hippocampus slices containing CA1 sub-region with α2C expression of both Adra2c-KO/lacZ-KI mutant mice (backcrossed to C57BL/6 for more than seven generations) and control mice were characterized by electrophysiology. Functional significance of α2C-AR in the induction and maintenance of hippocampal LTP was explored by extra-cellular slice recording in CA3-CA1 Schaffer’s collateral pathway. Preliminary results indicated that the induction of LTP is not affected by α2C-AR deficiency in homozygous mutants when compared to wild type littermate control (C57BL/6). However, with a four-train high-frequency stimulation (HFS, 100Hz) tetanus induction protocol, LTP manifested either in population spike or fEPSP mode, was substantially reduced not only in the early (60 min) but also in the late (180 min) phases in α2C-AR-null mice. Furthermore, significant difference in input/output curve was noted between α2C-AR-null and control. However, paired-pulse facilitation indicative of pre-synaptic short-term plasticity is not affected by α2C-AR deficiency. The modulatory effects of NE mediated through α2C-AR on basal level of synaptic activity and LTP were examined using selective agonist of α2 adrenoceptor, i.e. medetomidine. Dose-response studies of medetomidine, as measured by population spike, indicated the presence of significant difference between α2C-AR-null and wild-type mice. The data indicated that at low concentration, i.e., 100nM, medetomidine increases population spike height in hippocampus CA1 region in wild type controls whereas its effect is significantly lower in α2C-AR-null. LTP was diminished under high dose of medetomidine (1μM) in wild-type mice. As α2B-AR is not expressed in hippocampus, the specificity of the effects observed is investigated by inclusion of specific antagonist of α2A-AR. Simultaneous perfusion of medetomidine and BRL44408 indicated that activating α2C-AR might enhance the early-phase LTP. The results thereby suggest that NE may modulate LTP in hippocampus via α2C-AR. To correlate the phenotypic trait of aggression with emotional memory, hippocampus LTP elicited immediately after the impulsive attack against intruder on the 5th day of scheduled challenge was examined. α2C-AR-null mice subjected to the isolation-induced, multiple-intrusion aggression paradigm exhibited a significantly enhanced and lasting LTP in contrast to naïve or isolation-only groups. Another phenotypic trait of α2C-AR-null mice was blunted cocaine-CPP. After CPP the mutant mice brain slices exhibit attenuated LTP the same as those in the drug-naïve group, whereas cocaine-responsive wild-type mice show more enhanced LTP than those in the drug-naïve group. The involvements of hippocampus α2C-AR in emotional memory and drug addiction are thereby implicated.