Function and Regulation of CREB Family Transcription Factors in the Nervous System

Flavonoids: antioxidants or signalling molecules?

To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Lynch, MA. Long-Term Potentiation and Memory. Physiol Rev 84: 87–136, 2004; 10.1152/physrev.00014.2003.—One of the most significant challenges in neuroscience is to identify the cellular and molecu...

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Long-Term Potentiation and Memory

Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications.

Mechanisms of fear extinction

A Role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala

Memory consolidation is mediated by new protein synthesis. However, the transcriptional pathways induced in neurons by behavioral training that activate gene responses have yet to be fully delineated. We have previously shown that nuclear factor kappaB (NF-kappaB) is activated in the amygdala after fear conditioning. Here we report that fear conditioning resulted in an increase in histone acetyl-transferase activity, the association between NF-kappaB p65 and CBP, and the increase in acetylated p65. Pretreating animals with histone deacetylase (HDAC) inhibitors prolonged the nuclear expression of acetyl-p65 and increased its DNA binding activity. Consistent with these results, HDAC inhibitors enhanced long-term but not short-term fear memory, and this effect was attenuated by kappaB decoy DNA, whereas scrambled DNA was without effect. This study provides evidence that HDAC-mediated deacetylation functions as an intranuclear molecular switch culminating in the termination of NF-kappaB transcriptional response that is involved in the formation of fear memory.

Acetylation of Nuclear Factor-κB in Rat Amygdala Improves Long-Term but not Short-Term Retention of Fear Memory

A Requirement of Nuclear Factor-κB Activation in Fear-potentiated Startle

Glutamate preconditioning prevents neuronal death induced by combined oxygen-glucose deprivation in cultured cortical neurons

The metabotropic glutamate receptors (mGluRs) are G-proteincoupled receptors whose activation modulates neural activity via their linkage to multiple second-messenger systems (Pin and Duvoisin 1995; Anwyl 1999). Eight mGluRs have been cloned and classified into three groups based on their sequence homologies, signal transduction mechanisms, and agonist pharmacology (Nakanishi 1992; Pin and Duvoisin 1995). Group I (mGluR1 and mGluR5) receptors stimulate phosphatidylinositol hydrolysis, whereas group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, and mGluR8) receptors are negatively coupled to cAMP production. The group II mGluRs are implicated as negative feedback autoreceptors to modulate neurotransmission by presynaptic mechanisms (Pin and Duvoisin 1995). In situ hybridization and immunohistochemical studies of rat brain have revealed that the intense mGluR II-like immunoreactivity was seen predominantly in the cortical and limbic regions including the amygdala (Neki et al. 1996; Schaffhauser et al. 1998), suggesting that these receptors may modulate higher CNS functions such as emotion and cognition. Indeed, mGluR II agonists have been shown to inhibit the release of glutamate in vivo (Battaglia et al. 1997) and exhibit potent anxiolytic effects in rats (Helton et al. 1998). These compounds also ameliorated the symptoms of nicotine withdrawal (Helton et al. 1997) and lactate-induced panic responses (Shekhar and Keim 2000). Moreover, mice lacking mGluR II display impaired hippocampal mossy fiber long-term depression (LTD) (Yokoi et al. 1996). In external capsule (EC)-basolateral amygdala synapses, it has been shown that low-frequency stimulation (LFS) induced long-term potentiation (LTP), whereas brief high-frequency stimulation (HFS) evoked short-term potentiation that generally decayed within 10 min. When LFS was applied after recovery from the short-term potentiating effect of HFS, there was an initial transient enhancement followed by LTD. The switch in the direction of the enduring change in synaptic strength required activation of mGluR II (Li et al. 1998).

LTP of synaptic responses could be reversed by LFS of afferent fibers, a phenomenon termed “depotentiation” (Barrionuevo et al. 1980; Staubli and Chun 1996). Previous studies indicated that LTP of synapses from auditory thalamus and cortex to the lateral amygdala (LA) underlay the encoding of fear memory (McKernan and Shinnick-Gallagher 1997; Rogan et al. 1997). Yet, it is not clear whether depotentiation contributes to behavioral extinction of fear memory. In the present study, we obtained evidence that activation of mGluR II induces depotentiation in rat amygdala slices. This chemical depotentiation is independent of NMDA receptor, L-type Ca++ channels, and calcineurin activity, but requires presynaptic activity and extracellular Ca++. By behavioral tests, we further demonstrate that administration of mGluR II agonists to the LA or basolateral amygdala (BLA) blocks the consolidation of fear memory measured with fear-potentiated startle.

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Chia Ho Lin

Papers

A Role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala

Acetylation of Nuclear Factor-κB in Rat Amygdala Improves Long-Term but not Short-Term Retention of Fear Memory

A Requirement of Nuclear Factor-κB Activation in Fear-potentiated Startle

Glutamate preconditioning prevents neuronal death induced by combined oxygen-glucose deprivation in cultured cortical neurons

Activation of group II metabotropic glutamate receptors induces depotentiation in amygdala slices and reduces fear-potentiated startle in rats