A Mitogen-Activated Protein Kinase Cascade in the CA1/CA2 Subfield of the Dorsal Hippocampus Is Essential for Long-Term Spatial Memory

Abstract

Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. However, the molecular mechanisms underlying long-term spatial memory are poorly understood. In this study, we show that mitogen-activated protein kinase (MAPK, also called ERK) is activated in the dorsal, but not the ventral, hippocampus of rats after training in a spatial memory task, the Morris water maze. The activation was expressed as enhanced phosphorylation of MAPK in the pyramidal neurons of the CA1/CA2 subfield. In contrast, no increase in the percentage of phospho-MAPK-positive cells was detected in either the CA3 subfield or the dentate gyrus. The enhanced phosphorylation was observed only after multiple training trials but not after a single trial or after multiple trials in which the location of the target platform was randomly changed between each trial. Inhibition of the MAPK/ERK cascade in dorsal hippocampi did not impair acquisition, but blocked the formation of long-term spatial memory. In contrast, intrahippocampal infusion of SB203580, a specific inhibitor of the stress-activated MAPK (p38 MAPK), did not interfere with memory storage. These results demonstrate a MAPK-mediated cellular event in the CA1/CA2 subfields of the dorsal hippocampus that is critical for long-term spatial memory.

Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

“…Rats were anesthetized (50 mg/kg ketamine and 6 mg/kg xylazine) and placed in a stereotaxic holder (Stoelting, Wood Dale, IL). 22-Gauge guide cannulae (22-gauge) (Plastics One, Roanoke, VA) were implanted bilaterally into the CA1 subregion of the hippocampus using the following coordinates: AP, À3.3 mm from Bregma; ML, 72.0 mm from the midline; DV, À2.5 mm from dura (Blum et al, 1999;Paxinos and Watson, 1986). At 1 week after surgery, rats resumed daily sessions (the radial-arm maze task) or started training (the step-through task).…”

“…Conversely, in F442A cells, activation of ERK with epidermal growth factor (EGF) increases cAMP by inhibiting a PDE4 isoenzyme (Hoffmann et al, 1999). Consistently, crosstalk exists between cAMP and ERK signaling in the CA1 subregion of the hippocampus (Patterson et al, 2001;Stork and Schmitt, 2002), which is involved in the mediation of synaptic plasticity (Patterson et al, 2001;Roberson et al, 1999) and ERK signalingmediated long-term memory (Blum et al, 1999). Further, PDE4 isoemzymes are phosphorylated and regulated by ERK2.…”

“…Activation of ERK signaling enhances the induction of longterm-synaptic facilitation as well as long-term memory (Purcell et al, 2003). Conversely, inhibition of ERK signaling in the dorsal hippocampus blocks the formation of longterm memory, but not acquisition of short-term memory (Blum et al, 1999;Sharma et al, 2003). Further, both signaling pathways interact with each other.…”

Differential and Region-Specific Activation of Mitogen-Activated Protein Kinases Following Chronic Administration of Phencyclidine in Rat Brain

“…They can be activated in response to nerve growth factor , electroconvulsive shock (Baraban et al 1993;Kang et al 1994;, and glutamate receptor stimulation (Bading and Greenberg 1991;Fiore et al 1993a;Kawasaki et al 1999). Moreover, recent studies have linked the MAP kinase cascade to important brain functions, such as memory consolidation and long-term neuronal plasticity (Berman et al 1998;Blum et al 1999;Impey et al 1999). Two other classes of MAP kinases, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38, are activated by various stress stimuli, including ultraviolet irradiation, inflammatory cytokines and osmotic shock (Han et al 1994;Rouse et al 1994;Freshney et al 1994;Rosette and Karin 1996;Lewis et al 1998).…”

Differential activation of extracellular signal-regulated kinase 1 and a related complex in neuronal nuclei

“…As ERKs are thought to participate in regulating cellular transcriptional responses (Waltereit et al 2001), how the active enzyme might differentially regulate transcriptional programs induced with synaptic activity (moderately depolarizing) as distinct from potassium (severely depolarizing) stimulation is unknown; ERK is activated in both situations. In one case, ERK would be activated with normal synaptic activity in the brain, possibly during learning (Blum et al 1999), and in the other only under pathological conditions such as migraine aura, which is now thought to be due to a spreading-depression like phenomenon (Sanchez-del-Rio et al 2004). Other calcium-activated enzymes and transcription factor phosphorylation events might play a role in distinguishing the two cases, but they too are typically activated with both potassium and synaptic stimulation (Bito et al 1996).…”