Persistent Synaptic Plasticity Research Articles

The Role of Extracellular Regulated Kinases I/II in Late-Phase Long-Term Potentiation

Extracellular regulated kinases (ERKI/II), members of the mitogen-activated protein kinase family, play a role in long-term memory and long-term potentiation (LTP). ERKI/II is required for the induction of the early phase of LTP, and we show that it is also required for the late phase of LTP in area CA1 in vitro, induced by a protocol of brief, repeated 100 Hz trains. We also show that ERKI/II is necessary for the upregulation of the proteins encoded by the immediate early genes Zif268 and Homer after the induction of LTP in the dentate gyrus by tetanic stimulation of the perforant path in vivo or by BDNF stimulation of primary cortical cultures. To test whether the induction of persistent synaptic plasticity by stimuli such as BDNF is associated with nuclear translocation of ERKI/II, we expressed enhanced green fluorescent protein (EGFP)-ERKII in PC12 cell lines and primary cortical cultures. In both preparations, we observed translocation of EGFP-ERKII from the cytoplasm to the nucleus in cells exposed to neurotrophic factors. Our results suggest that the induction of late LTP involves translocation of ERKI/II to the nucleus in which it activates the transcription of immediate early genes. The ability to visualize the cellular redistribution of ERKII after induction of long-term synaptic plasticity may provide a method for visualizing neuronal circuits underlying information storage in the brain in vivo.

The role of extracellular regulated kinases I/II in late-phase long-term potentiation.

Extracellular regulated kinases (ERKI/II), members of the mitogen-activated protein kinase family, play a role in long-term memory and long-term potentiation (LTP). ERKI/II is required for the induction of the early phase of LTP, and we show that it is also required for the late phase of LTP in area CA1 in vitro, induced by a protocol of brief, repeated 100 Hz trains. We also show that ERKI/II is necessary for the upregulation of the proteins encoded by the immediate early genes Zif268 and Homer after the induction of LTP in the dentate gyrus by tetanic stimulation of the perforant path in vivo or by BDNF stimulation of primary cortical cultures. To test whether the induction of persistent synaptic plasticity by stimuli such as BDNF is associated with nuclear translocation of ERKI/II, we expressed enhanced green fluorescent protein (EGFP)-ERKII in PC12 cell lines and primary cortical cultures. In both preparations, we observed translocation of EGFP-ERKII from the cytoplasm to the nucleus in cells exposed to neurotrophic factors. Our results suggest that the induction of late LTP involves translocation of ERKI/II to the nucleus in which it activates the transcription of immediate early genes. The ability to visualize the cellular redistribution of ERKII after induction of long-term synaptic plasticity may provide a method for visualizing neuronal circuits underlying information storage in the brain in vivo.

Arg3.1/Arc mRNA Induction by Ca2+and cAMP Requires Protein Kinase A and Mitogen-Activated Protein Kinase/Extracellular Regulated Kinase Activation

Long-term potentiation (LTP) is a cellular model for persistent synaptic plasticity in the mammalian brain. Like several forms of memory, long-lasting LTP requires cAMP-mediated activation of protein kinase A (PKA) and is dependent on gene transcription. Consequently, activity-dependent genes such as c-fos that contain cAMP response elements (CREs) in their 5' regulatory region have been studied intensely. More recently, arg3.1/arc became of interest, because after synaptic stimulation, arg3.1/arc mRNA is rapidly induced and distributed to dendritic processes and may be locally translated there to facilitate synapse-specific modifications. However, to date nothing is known about the signaling mechanisms involved in the induction of this gene. Here we report that arg3.1/arc is robustly induced with LTP stimulation even at intensities that are not sufficient to activate c-fos expression. Unlike c-fos, the 5' regulatory region of arg3.1/arc does not contain a CRE consensus sequence and arg3.1/arc is unresponsive to cAMP in NIH3T3 and Neuro2a cells. However, in PC12 cells and primary cultures of hippocampal neurons, arg3.1/arc can be induced by cAMP and calcium. This induction requires the activity of PKA and mitogen-activated protein kinase, suggesting a neuron-specific pathway for the activation of arg3.1/arc expression.

Metaplasticity: the plasticity of synaptic plasticity

In thi paper, we review experimental evidence for a novel form of persistent synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic or cellular activity, but it is not necessarilly expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifest as a change in the ability to induce subsequent synaptic plasticity such as long-term potentiation or depression, Thus metaplasticity is higher-order form of synaptic plasticity. Metaplasticity might involve alterations in NMDA-receptor function in some cases, but there are many other candidate mechanisms. The induction of metaplasticity complicates the interpretation of many commonly studied aspects of synaptic plasticity, such as saturation and biochemical correlates.

Compensatory synaptic growth in the rod terminals as a sequel to partial photoreceptor cell loss in the retina of chimaeric mice.

In the retina of chimaeric mice of rd and wild-type genotypic combination, selective loss of rd/rd photoreceptor cells, after initial development, leads to a mosaic retina with variable amounts of normal photoreceptor cells present over the retinal surface. In some of the rod terminals of these retinas the synaptic complexes with the second order retinal neurons are seen to contain multiple synaptic ribbons and an increased number of profiles of the postsynaptic elements. These changes are observed only in the rod terminals and not in the cone pedicles. Computer aided three-dimensional reconstruction of the altered synapses shows that these changes result from an increase in the number of synaptic sites, characterized by multiplication of the synaptic ribbons and enlargement of the second order neuronal processes. A quantitative analysis of such synapses, based on serial electron micrographs, shows that these are most frequently located in the retinal regions of the chimaeric individuals that have suffered maximum photoreceptor cell loss. Thus synaptic growth appears to take place as a reaction to the reduction of afferent input to the postsynaptic components. These findings demonstrate persistent synaptic plasticity in the rod terminals of mammalian retina during the maturational phase of late postnatal development. Compensatory synaptic growth in the rod terminals, as recorded here, can have important implications for the maintenance of visual sensitivity in the diseased or ageing retina.

Long-term sensitization in Aplysia increases the number of presynaptic contacts onto the identified gill motor neuron L7.

We have used the gill and siphon withdrawal reflex of Aplysia to study the morphological basis of the persistent synaptic plasticity that underlies long-term sensitization. One critical locus for storage of the memory for sensitization is the set of monosynaptic connections between identified siphon sensory neurons and gill and siphon motor neurons. To complement previous morphological studies of the presynaptic terminals of identified sensory neurons, we examined the effects of long-term sensitization on the structure of an identified postsynaptic target--the gill motor neuron L7. We found an increase in the frequency, size, and vesicle complement of presynaptic contacts onto L7 processes in sensitized compared to control animals. Combined, these data indicate a striking increase in the percentage of the surface area of L7 that is occupied by synaptic contacts after long-term training. These results are consistent with our observations that sensitization produces an increase in the synapses that the sensory neurons make on their target cells and provide additional support for the hypothesis that changes in synapse number may represent a mechanism underlying long-term memory.

Morphological basis of long-term habituation and sensitization in Aplysia.

The morphological basis of the persistent synaptic plasticity that underlies long-term habituation and sensitization of the gill withdrawal reflex in Aplysia californica was explored by examining the fine structure of sensory neuron presynaptic terminals (the critical site of plasticity for the short-term forms of both types of learning) in control animals and in animals whose behavior had been modified by training. The number, size, and vesicle complement of sensory neuron active zones were larger in animals showing long-term sensitization than in control animals and smaller in animals showing long-term habituation. These changes are likely to represent an anatomical substrate for the memory consolidation of these tasks.