To investigate the role of CREB-mediated gene expression on the excitability of CA1 pyramidal neurons, we obtained intracellular recordings from pyramidal neurons of transgenic mice expressing a constitutively active form of CREB, VP16-CREB, in a regulated and restricted manner. We found that transgene expression increased the neuronal excitability and inhibited the slow and medium afterhyperpolarization currents. These changes may contribute to the reduced threshold for LTP observed in these mice. When strong transgene expression was turned on for prolonged period of time, these mice also showed a significant loss of hippocampal neurons and sporadic epileptic seizures. These deleterious effects were dose dependent and could be halted, but not reversed by turning off transgene expression. Our experiments reveal a new role for hippocampal CREB-mediated gene expression, identify the slow afterhyperpolarization as a primary target of CREB action, provide a new mouse model to investigate temporal lobe epilepsy and associated neurodegeneration, and illustrate the risks of cell death associated to a sustained manipulation of this pathway. As a result, our study has important implications for both the understanding of the cellular bases of learning and memory and the consideration of therapies targeted to the CREB pathway.
"Expression of active CREB in these neurons increased excitability, whereas downregulation of CREB by expressing dominant-negative CREB decreased excitability. The electrophysiological recordings from transgenic mice expressing a constitutively active form of CREB, VP16-CREB, showed that enhancing CREB activity increased the intrinsic excitability of hippocampal CA1 and basal amygdala pyramidal neurons (Lopez de Armentia et al., 2007; Viosca et al., 2009). Consistent with the observed CREB-induced increase in excitability, CREB function has also been reported to stimulate the expression of the voltagedependent Na + channel 1β subunit and inhibit the expression of the voltage-dependent K + channel K V 1.4 subunit (McClung and Nestler, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Despite considerable progress over the past several decades, our understanding of the mechanisms underlying memory encoding, storage, and expression in a complex neural network are far from complete. In particular, how some neurons rather than others are selectively engaged to encode memory remains largely unknown. Using virus-mediated gene delivery into a small subset of neurons in a given network, molecular imaging of neuronal activity, pharmacological perturbation of specific neurons' activity and animal behavior assays, recent studies have begun to provide insight into molecular and cellular mechanisms responsible for the selection of neurons for inclusion into a memory trace. Here, we focus on a review of recent findings supporting the hypothesis that the level of the transcription factor CREB (cAMP/Ca(2+)-response element binding protein) is a key factor governing which neurons are recruited to a given memory trace. These recent findings open a new perspective on memory trace at the neural circuit level and also raise many important questions. Future studies employing more advanced neurobiological techniques for targeting defined populations of neurons and manipulating their activity in time and space in a complex neural network will give answers to these newly emerging questions and extend our understanding of the neurobiological basis of the memory trace.
"The authors note that translating these findings will require a greater understanding of CREBmediated changes in neuronal morphology, as well as any deleterious effects from chronic upregulation of CREB expression. In fact, previous studies have shown that sustained overexpression of CREB in the CA1 region in mice leads to a significant loss of hippocampal neurons and sporadic epileptic seizures (Lopez de Armentia et al, 2007). Throughout the exploration of novel therapeutic strategies , it is important to acknowledge the limitations of familial, early-onset mouse models of AD. "
"On the other hand, cAMP appears to be a proconvulsant second messenger that exerts its effects particularly by activating cAMP-dependent protein kinase pathways. Cyclic AMP-induced protein kinase activation results in the phosphorylation of the cAMP response element binding protein (CREB), γ-aminobutyric acid A (GABA A ), and N-methyl-D-aspartic acid (NMDA) receptors (Jancic et al., 2009; Lan et al., 2001; Poisbeau et al., 1999; Westphal et al., 1999), which play important roles for seizuremediated processes (Bracey et al., 2009; Esteban et al., 2003; Lopez et al., 2007; Poisbeau et al., 1999). PDE enzymes consist of several subtypes that are distributed in different tissues. "
[Show abstract][Hide abstract] ABSTRACT: The present study shows interactive effects of pentoxifylline (PTX) as a phosphodiesterase (PDE) inhibitor, H-89 as a protein kinase A (PKA) inhibitor and bucladesine (db-cAMP) as a cAMP agonist on pentylenetetrazol (PTZ)-induced seizure in mice. Different doses of pentoxifylline (25, 50, 100 mg/kg), bucladesine (50, 100, 300 nM/mouse), and H-89 (0.05, 0.1, 0.2 mg/100g) were administered intraperitoneally (i.p.), 30 min before intravenous (i.v.) infusion of PTZ (0.5% w/v). In combination groups, the first and second components were injected 45 and 30 min before PTZ infusion. In all groups, the control animals received an appropriate volume of vehicle. Single administration of PTX had no significant effect on both seizure latency and threshold. Bucladesine significantly decreased seizure latency and threshold only at a high concentration (300 nM/mouse). Intraperitoneal administration of H-89 (0.2 mg/100g) significantly increased seizure latency and threshold in PTZ-treated animals. All applied doses of bucladesine in combination with PTX (50 mg/kg) caused a significant reduction in seizure latency. Pretreatment of animals with PTX (50 and 100 mg/kg) attenuated the anticonvulsant effect of H-89 (0.2 mg/100g) in PTZ-exposed animals. H-89 (0.05, 0.2 mg/100g) prevented the epileptogenic activity of bucladesine (300 nM) with significant increase of seizure latency and seizure threshold. In conclusion, we showed that seizure activities were affected by pentoxifylline, H-89 and bucladesine via interactions with intracellular cAMP and cGMP signaling pathways, cyclic nucleotide-dependent protein kinases, and related neurotransmitters.
European journal of pharmacology 09/2011; 670(2-3):464-70. DOI:10.1016/j.ejphar.2011.09.026 · 2.53 Impact Factor
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