A Novel Role for Extracellular Signal-Regulated Kinase in Maintaining Long-Term Memory-Relevant Excitability Changes

Abstract

Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the postburst afterhyperpolarization (AHP), which is generated by repetitive spike firing. AHP reduction is attributable to decreased conductance of a calciumdependent potassium current, the sI AHP . We have previously shown that such learning-induced AHP reduction is maintained by PKC activation. However, the molecular machinery underlying such long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the extracellular signal-regulated kinase I/II (ERKI/II) pathway, which is known to be crucial in learning, memory, and synaptic plasticity processes, is instrumental for the long-term maintenance of learning-induced AHP reduction. PD98059 or UO126, which selectively block MEK, the upstream kinase of ERK, increased the AHP in neurons from trained rats but not in neurons from naive and pseudo-trained rats. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls were abolished. This effect was not mediated by modulation of basic membrane properties. In accordance with its effect on neuronal excitability, the level of activated ERK in the membranal fraction was significantly higher in piriform cortex samples taken from trained rats. In addition, the PKC activator OAG (1-oleoyl-20acety-sn-glycerol), which was shown to reduce the AHP in neurons from control rats, had no effect on these neurons in the presence of PD98059. Our data show that ERK has a key role in maintaining long-lasting learning-induced enhancement of neuronal excitability.

Persistent ERK activation maintains learning-induced long-lasting modulation of synaptic connectivity

“…Here too, there is a mild increase in the activity level in the pseudo-trained group. As previously shown (Cohen-Matsliah et al 2007), the activity level of ERK in the total homogenate fraction, which is known to mediate many cellular events, is not enhanced after learning. This compartment-specific ERK activation, next to the cell membrane, supports the notion of its possible modulation of learning-induced synaptic transmission.…”

“…Previous studies have shown that olfactory learning-induced long-lasting enhancement of neuronal excitability is dependent on long-term persistent activation of a second messenger cascade that includes ERK and PKC (Cohen-Matsliah et al 2007). Here we show that these two key enzymes have also a pivotal role in maintaining learning-induced long-lasting enhancement of synaptic connectivity, as reflected by PPF reduction measured 3 d after learning.…”

“…We have previously shown that long-lasting learning-induced enhancement of intrinsic neuronal excitability is dependent on persistent activation of both ERK (Cohen-Matsliah et al 2007) and PKC (Seroussi et al 2002). The effect of PKC on neuronal excitability is abolished by blocking MEK, indicating that PKC is upstream relative to the ERK pathway in the sequence of kinase cascade, underlying long-lasting neuronal excitability (CohenMatsliah et al 2007).…”

“…ERK activation was found to be necessary for both induction and consolidation of LTP Sweatt 1996, 1997;Rosenblum et al 2000Rosenblum et al , 2002Di Cristo et al 2001;Selcher et al 2003). Moreover, persistent ERK activation is required for long-term maintenance of learning-induced enhancement of intrinsic neuronal excitability (Cohen-Matsliah et al 2007).…”

Learning-induced modulation of the GABAB-mediated inhibitory synaptic transmission: mechanisms and functional significance

“…Such rule learning is accompanied by a series of pre-and postsynaptic cellular modifications in layer II pyramidal neurons of the piriform cortex. Long-term enhancement occurs in the three components controlling neuronal activation: the excitatory synaptic drive mainly mediated by glutamate receptors (Knafo et al 2005;Saar et al 1999Saar et al , 2002, the intrinsic neuronal excitability (Cohen-Matsliah et al 2007;Saar et al 1998Saar et al , 2001, and synaptic inhibition mediated by GABA A receptors (Brosh and Barkai 2009). These modifications are widespread throughout the piriform cortex network; physiological and morphological modifications are found in most of the studied neurons (Brosh and Barkai 2009;Knafo et al 2005;Saar et al 1998Saar et al , 1999Saar et al , 2002Saar and Barkai 2003).…”