Postsynaptic factors in the expression of long-term potentiation (LTP): increased glutamate receptor binding following LTP induction in vivo.

Abstract

Several lines of evidence indicate that LTP in the hippocampus is associated with a change in the properties of postsynaptic glutamate receptors. In the present study, we used quantitative autoradiography to examine the binding properties of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate subclasses of glutamate receptors in frozen brain sections obtained from rats in which perforant-path LTP LTP of excitatory synaptic transmission in the hippocampus is an enduring form of synaptic enhancement that may underlie some forms of mammalian learning and memory (1, 2). While consensus has been reached on the cellular mechanisms involved in triggering LTP, the nature of the persistent synaptic modification underlying the expression of LTP is still a matter of debate (3). There is a growing body of evidence that LTP is expressed, at least in part, by a persistent modification of postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, a subclass of ionotropic glutamate receptors (4-9). This modification may be variously expressed as an increase in the binding affinity of AMPA receptors, an increase in the number of AMPA binding sites, or a change in the kinetics of AMPA receptor-gated ion channels. To further restrict these possibilities, we have examined the binding properties of postsynaptic AMPA and N-methyl-D-aspartate (NMDA) receptors (another subclass ofionotropic glutamate receptors) in frozen brain sections following perforant-path LTP induction in vivo. We report a selective increase in hippocampal AMPA receptor binding following perforant-path LTP induction that is apparently mediated by an increase in the number of AMPA binding sites. These results suggest that a change in the binding properties of AMPA receptors contributes to the enhanced synaptic transmission observed at hippocampal synapses following LTP induction.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. MATERIALS AND METHODSSubjects and Surgery. Adult male Long-Evans rats (250-300 g) were anesthetized with an i.p. injection of sodium pentobarbital (65 mg/kg) and implanted with a recording electrode in the hilus of the dentate gyrus and a bipolar stimulating electrode in the perforant path (9). The electrodes consisted of Epoxylite-coated stainless-steel pins with the recording and stimulating surfaces formed by removing the insulation at the tips. The electrode tip lengths were 50 and 500 ,um for recording and stimulating electrodes, respectively.Acute Electrophysiology. All electrophysiological testing was performed under surgical anesthesia. Extracellular field potentials evoked by single-pulse perforant-path stimulation pulses (0.1 msec, 0.05 Hz) were recorded in the dentate gyrus during a 10-min interval before and a 60-min interval following high-or low-frequency perforant-path stimulation (HFS or LFS). Fig. 1A repr...

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…Hence, CX546 may represent a new class of potential antipsychotics but with different mechanisms of action from conventional antipsychotics. AMPAR number and sensitivity to agonists is increased upon induction of LTP (Maren et al, 1993) as well as recruitment of silent AMPA synapses was demonstrated upon induction of LTP in electrophysiological experiments (Isaac et al, 1995). LTP is frequently suggested as a synaptic marker of associative memory in the hippocampus (Morris et al, 1990), and it has also been demonstrated in the amygdala (LeDoux, 2000).…”

Differential expression of short-term potentiation by AMPA and NMDA receptors in dentate gyrus.

“…For hippocampal synapses at which N-methyl-n-aspartate (NMDA) and 0L-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamatergic receptors coexist, it is now established that the NMDA receptor subtype plays a critical role in the induction process: Excitatory synaptic input must depolarize the postsynaptic neuron to an extent that there is substantial unblocking of NMDA receptor channels (Mayer 1984;Nowak et al 1984;Mayer and Westbrook 1987). There is less agreement with respect to the mechanisms underlying LTP expression, though one of the more widely considered hypotheses is that the maintained expression of LTP reflects a modification of AMPA receptor channels and thus, is postsynaptic in origin (Lynch and Baudry 1984;Maren et al 1993;Tocco et al 1994). This hypothesis is supported by the observation that, following the induction of LTP and subsequent pharmacological blockade of AMPA receptors, the residual NMDA receptor-mediated component of synaptic responses shows only a small magnitude of potentiation compared with that exhibited by the AMPA receptor-mediated component.…”

A Review of Glutamate Receptors I: Current Understanding of Their Biology

“…This Ca ++ influx triggers a cascade of secondary messengers which ultimately activate a number of enzymes such as protein kinase C (PKC), phospholipase A2 (PLA2), phospholipase C (PLC), Ca ++ -calmodulindependent protein kinase II (CaM kinase II), and others [272][273][274][275][276][277][278] . Consequently, these processes lead to fixation of changes in postsynaptic AMPA receptors such as an increase in their affinity and number [279][280][281][282][283] , and possibly through retrograde signals from arachidonic acid and nitric oxide 284 , modulate presynaptic glutamatergic terminals influencing [285][286][287][288][289][290] .…”