Shanshan Li

Date of Award

3-27-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Saobo Lei

Abstract

Neurotensin (NT) is a tridecapeptide that interacts with three NT receptors, NTS1, NTS2 and NTS3. NT has been reported to modulate GABA release in various brain regions under both physiological and pathological conditions. A beneficial role for NT in correcting GABA dysfunction/deficiency has been implied. However, the cellular and molecular mechanisms underlying NT-induced increases in GABAergic function remain ill-defined. Here, we first examined the effects of NT on GABAergic transmission and the underlying cellular and signaling mechanisms in the hippocampus of juvenile rats. We found that NT dose-dependently increased sIPSC frequency in CA1 pyramidal neurons without affecting the amplitude of sIPSCs. Triple immunofluorescent staining demonstrated the expression of NTS1 on recorded GABAergic interneurons. NT increased action potential firing rates and decreased afterhyperpolarization (AHP) amplitudes in identified CA1 interneurons. Blockade of L-type calcium channels abolished NT-induced increases in action potential firing rates and reduction in AHP amplitudes suggesting that NT-induced increases in GABAergic activity are mediated by L-type Ca2+ channels. We also examined the effect of NT on GABAergic activity in the CA1 region of hippocampus from juvenile, young-adult and aged rats. We found that NT significantly increased sIPSC frequency of CA1 pyramidal neurons in both juvenile and aged rats, but not in young-adult rats. The NTS1 selective antagonist, SR98692, blocked the effects. There was also no significant change of mIPSC frequency and amplitude recorded from CA1 pyramidal neurons. The numbers of NTS1-immunopositive GABAergic neuron were significantly lower in young-adult rats compared with juvenile and aged rats. Western blot analysis of GAD protein levels indicated GABA neurons expression was lower in the hippocampus in juvenile and aged rats than young-adult rats. These results were consistent with the electrophysiological recordings. These indicate GABAergic activity was low in both juvenile and aged rats. Our study indicated that NT increased GABAergic activity only when there was GABA deficiency/dysfunction, which provided strong evidence that NT could be an important factor to improve GABA system activity in both aging and/or pathological conditions when and where GABA deficiency/dysfunction is present.

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