ABSTRACT
As the best-studied form of vertebrate synaptic plasticity, NMDA-receptor dependent long-term potentiation (NMDAR-LTP) has long been considered a leading candidate for a cellular locus for some aspects of learning and memory. However, assigning a specific role for this form of plasticity in learning and memory has proven surprisingly difficult. Two issues have contributed to this difficulty. First, a large number of molecules have been shown to in some way mediate or modulate not only NMDAR-LTP but also many forms of plasticity. Indeed, it is increasingly clear that multiple induction and maintenance mechanisms for plasticity exist, often at the same synapse. Second, linking cellular events to behavioral function has been hindered by a lack of sufficiently precise tools. In this review, we will discuss some of the proposed mechanisms of induction and maintenance of changes in synaptic efficacy and their regulation in the context of an attempt to understand their roles in animal behavior. Further, we will discuss recently developed genetic techniques, specifically, inducible transgenic models, which now allow more precise manipulations in the study of the roles plasticity plays in learning and memory.
Subject(s)
Behavior, Animal/physiology , Neuronal Plasticity/genetics , Animals , Genetics, Behavioral , Hippocampus/physiology , Long-Term Potentiation/genetics , Mice , Mice, Knockout/genetics , Mice, Transgenic/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Species SpecificityABSTRACT
The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. The alpha(2)-adrenergic receptors (alpha(2)-ARs) modulate norepinephrine release, as well as the release of serotonin and other neurotransmitters, and are therefore potential targets for antidepressant and anxiolytic drug development. The current studies were undertaken to examine the role of the alpha(2A) subtype of alpha(2)-AR in mouse behavioral models of depression and anxiety. We have observed that the genetic knock-out of the alpha(2A)-AR makes mice less active in a modified version of Porsolt's forced swim test and insensitive to the antidepressant effects of the tricyclic drug imipramine in this paradigm. Furthermore, alpha(2A)-AR knock-out mice appear more anxious than wild-type C57 Bl/6 mice in the rearing and light-dark models of anxiety after injection stress. These findings suggest that the alpha(2A)-AR may play a protective role in some forms of depression and anxiety and that the antidepressant effects of imipramine may be mediated by the alpha(2A)-AR.
Subject(s)
Anxiety/metabolism , Depression/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Darkness , Disease Models, Animal , Female , Fluoxetine/pharmacology , Imipramine/pharmacology , Light , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Adrenergic, alpha-2/deficiency , Receptors, Adrenergic, alpha-2/genetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Spatial Behavior/drug effects , Spatial Behavior/physiology , Stress, Physiological/metabolism , Swimming/physiologyABSTRACT
Agonist-elicited receptor sequestration is strikingly different for the alpha(2A)- versus alpha(2B)-adrenergic receptor (alpha(2)-AR) subtypes; the alpha(2B)-AR undergoes rapid and extensive disappearance from the HEK 293 cell surface, whereas the alpha(2A)-AR does not (Daunt, D. A., Hurt, C., Hein, L., Kallio, J., Feng, F., and Kobilka, B. K. (1997) Mol. Pharmacol. 51, 711-720; Eason, M. G., and Liggett, S. B. (1992) J. Biol. Chem. 267, 25473-25479). Since recent reports suggest that endocytosis is required for some G protein-coupled receptors to stimulate the mitogen-activated protein (MAP) kinase cascade (Daaka, Y., Luttrell, L. M., Ahn, S., Della Rocca, G. J., Ferguson, S. S., Caron, M. G., and Lefkowitz, R. J. (1998) J. Biol. Chem. 273, 685-688; Luttrell, L. M., Daaka, Y., Della Rocca, G. J., and Lefkowitz, R. J. (1997) J. Biol. Chem. 272, 31648-31656; Ignatova, E. G., Belcheva, M. M., Bohn, L. M., Neuman, M. C., and Coscia, C. J. (1999) J. Neurosci. 19, 56-63), we evaluated the differential ability of these two subtypes to activate MAP kinase. We observed no correlation between subtype-dependent agonist-elicited receptor redistribution and receptor activation of the MAP kinase cascade. Furthermore, incubation of cells with K(+)-depleted medium eliminated alpha(2B)-AR internalization but did not eliminate MAP kinase activation, suggesting that receptor internalization is not a general prerequisite for activation of the MAP kinase cascade via G(i)-coupled receptors. We also noted that neither dominant negative dynamin (K44A) nor concanavalin A treatment dramatically altered MAP kinase activation or receptor redistribution, indicating that these experimental tools do not universally block G protein-coupled receptor internalization.
