Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis

Abstract

Long-term potentiation (LTP) is a form of synaptic plasticity that has been extensively studied as a putative mechanism underlying learning and memory. A late phase of LTP occurring 3-5 hours after stimulation and depending on transcription, protein synthesis and cyclic-AMP-dependent protein kinase (protein kinase A, or PKA) has been described, but it is not known whether transcription of presynaptic and/or postsynaptic genes is required to support late-phase LTP. Here we show that late-phase LTP can be obtained in rat hippocampal CA1 mini-slices in which the cell bodies of presynaptic Schaffer collateral/commissural fibres are removed. Thus, transcription of presynaptic genes is not necessary to support maintenance of late-phase LTP. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor is the predominant mediator of the ionotropic response to synaptically released glutamate in the hippocampus and it has been implicated in LTP maintenance. We find that synthesis of AMPA receptor subunits is increased three hours after LTP induction: this effect on the synthesis of the AMPA receptor is blocked by inhibitors of PKA and of transcription. Our results support the idea of a postsynaptic mechanism maintaining late-phase LTP, in which AMPA receptor synthesis is increased as a result of PKA-dependent gene transcription.

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

“…Activity-dependent recruitment of AMPARs is well described (Liao et al, 2001;O'Brien et al, 1998;Turrigiano, 2000) and is a final common pathway mediating activity-dependent changes in synaptic efficacy at CA1 excitatory synapses both in vivo and in vitro (Baudry and Lynch, 2001;Liao et al, 1995;Lledo et al, 1998;Nayak et al, 1998;Zamanillo et al, 1999). Activitydependent changes in synaptic function are primarily the consequence of intracellular Ca 2 þ -dependent biochemical cascades and involve changes in synaptic AMPAR number and/or function (Hayashi et al, 2000;Song and Huganir, 2002).…”

Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

“…Long-lasting LTP, induced by a stimulation regimen similar to ours, was blocked when apical dendrites were severed from the cell bodies of CA1 pyramidal neurons in slices (Frey et al, 1989). Because LTP induced by this multitrain stimulation regimen is PKA dependent (Frey et al, 1993;Matthies and Reymann, 1993) and also requires the PKA-dependent synthesis of postsynaptic AMPA receptors for its expression (Nayak et al, 1998), these considerations support our hypothesis that postsynaptic mechanisms, including the activation of postsynaptic PKA, are critical for the expression of long-lasting, tetanus-induced LTP.…”

Protein synthesis in the dendrite

“…Translation inhibitors blocked this stimulation-induced synthesis (Osten et al 1996). In addition, it was reported that LTP induction stimulated the synthesis of glutamate receptor subunits GluR1 and GluR2/3, in a cAMP-signalling-mediated, transcriptiondependent manner (Nayak et al 1998). It would be interesting to see if synthesis of these plasticity-related proteins after LTP induction involves local translation mechanisms.…”