[show abstract][hide abstract] ABSTRACT: Beta-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that beta-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, beta-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2(-/-) mice exhibit impaired conditioned fear memory and long-term potentiation at the lateral amygdalar synapses. Moreover, expression of the beta-arrestin-2 in the lateral amygdala of Arrb2(-/-) mice, but not its mutant form that is incapable of binding PDE-4, restores basal PKA activity and rescues conditioned fear memory. Taken together, our data demonstrate that the feedback regulation of amygdalar PKA activation by beta-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory.
Proceedings of the National Academy of Sciences 12/2009; 106(51):21918-23. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepinephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically administered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cingulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibitory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at '0' or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. Intra-BLA or intra-ACC infusion of MPD '0' h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consolidation of inhibitory avoidance memory.
Science in China Series C Life Sciences 10/2008; 51(9):808-13. · 1.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sac domain-containing proteins belong to a newly identified family of phosphoinositide phosphatases (the PIPPase family). Despite well-characterized enzymatic activity, the biological functions of this mammalian Sac domain PIPPase family remain largely unknown. We identified a novel Sac domain-containing protein, rat Sac3 (rSac3), which is widely expressed in various tissues and localized to the endoplasmic reticulum, Golgi complex and recycling endosomes. rSac3 displays PIPPase activity with PI(3)P, PI(4)P and PI(3,5)P(2) as substrates in vitro, and a mutation in the catalytic core of the Sac domain abolishes its enzymatic activity. The expression of rSac3 is upregulated during nerve growth factor (NGF)-stimulated PC12 cell neuronal differentiation, and overexpression of this protein promotes neurite outgrowth in PC12 cells. Conversely, inhibition of rSac3 expression by antisense oligonucleotides reduces neurite outgrowth of NGF-stimulated PC12 cells, and the active site mutation of rSac3 eliminates its neurite-outgrowth-promoting activity. These results indicate that rSac3 promotes neurite outgrowth in differentiating neurons through its PIPPase activity, suggesting that Sac domain PIPPase proteins may participate in forward membrane trafficking from the endoplasmic reticulum and Golgi complex to the plasma membrane, and may function as regulators of this crucial process of neuronal cell growth and differentiation.
Cell Research 12/2007; 17(11):919-32. · 10.53 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is widely accepted that early environmental influences may affect the behavior of adult animals and their responses to psychotropic drugs. Rearing animals in isolation is a relevant paradigm for studying early life stress and for understanding the development of certain neurological and psychiatric diseases. The present study evaluated the effect of adolescent isolation on intravenous cocaine self-administration in adult rats. Male Sprague-Dawley rats were raised from postnatal day 22 to 55 either alone (isolated) or in groups of four per cage (grouped). Then, rats were trained for cocaine self-administration. Our results showed that both isolated and grouped rats acquired stable cocaine self-administration during 5 days of self-administration training. Numbers of both lever presses and cocaine infusions in isolated rats were significantly more than those in grouped rats. Especially, numbers of incorrect lever presses in isolated rats were significantly more than those in grouped rats. In addition, the intervals of inter-reinforcement for cocaine in isolated rats were significantly shorter as compared with grouped rats. These results indicate that rats with adolescent isolation experience have enhanced cocaine self-administration behavior.
Pharmacology Biochemistry and Behavior 01/2006; 82(4):673-7. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: As a synaptosomal protein, SNAP-25 plays a role in a number of neuronal functions including axonal growth, dendrite formation, fusion of synaptic vesicles with membrane and the expression of long-term potentiation (LTP) in the hippocampus. Using a learning/memory behavior screening, we identified SNAP-25 as one of the differentially expressed genes in the hippocampus upon behavioral training. The inhibition of SNAP-25 with intracerebroventricular antisense oligonucleotide caused a deficit in long- but not short-term memory for step-down inhibitory avoidance. Intra-CA1 infusion of the SNAP-25 antisense oligonucleotide impaired long-term contextual fear memory and spatial memory and interfered with the LTP of synaptic transmission in the CA1 region. The inhibitory effect on LTP was not mediated by a pre-synaptic mechanism because paired pulse facilitation of synaptic transmission was not affected after administration of the antisense oligonucleotide. Together, the results suggest that SNAP-25 in the CA1 region is involved in memory consolidation.
European Journal of Neuroscience 10/2004; 20(6):1593-603. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Activation of beta-adrenoceptors in area CA1 of the hippocampus facilitates in vitro long-term potentiation (LTP) in this region. However, it is unclear if in vivo LTP in area CA1 and hippocampus-dependent learning are subjected to beta-adrenergic regulation. To address this question, we investigated the effects of the beta-adrenergic agonist L-isoproterenol or antagonist DL-propranolol on in vivo LTP of area CA1 and the spatial learning in Morris water maze. In the presence of L-isoproterenol (through local infusion into area CA1), the theta-pulse stimulation with the parameter of 10 Hz, 150 pulses/train, 1 train, a frequency weakly modifying synaptic strength, induced a robust LTP, and this effect was blocked when DL-propranolol was co-administered. By contrast, the theta-pulse stimulation with the parameter of 5 Hz, 150 pulses/train, 3 trains, a frequency strongly modifying synaptic strength, induced a significantly smaller LTP when DL-propranolol was administered into area CA1. Accordingly, DL-propranolol impaired the spatial learning in the water maze when infused into area CA1 20 min pretraining. Compared with control rats, the DL-propranolol-treated rats showed significantly slower learning in the water maze and subsequently exhibited poor memory retention at 24-h test. These results suggest that beta-adrenoceptors in area CA1 are involved in regulating in vivo synaptic plasticity of this area and are important for spatial learning.
Science in China Series C Life Sciences 01/2004; 46(6):605-14. · 1.61 Impact Factor