Facilitation of glutamate receptors enhances memory.

Abstract

A benzamide drug that crosses the bloodbrain barrier and facilitates DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses was tested for its effects on memory in three behavioral tasks. The compound reversibly increased the amplitude and prolonged the duration of field excitatory postsynaptic potentials in hippocampal slices and produced comparable effects in the dentate gyrus in situ after intraperitoneal iDjections. Rats in jected with the drug 30 min prior to being given a suboptimal number of training trials in a two-odor discrimination task were more likely than controls to select the correct odor in a retention test carried out 96 hr later. Evidence for improved memory was also obtained in a water maze task in which rats were given only four trials to find a submerged platform in the presence of spatial cues; animals injected with the drug 30 min before the training session were significantly faster than vehicle-inJected controls in returning to the platform location when tested 24 hr after training. Finally, the drug produced positive effects in a radial maze test of short-term memory. Well trained rats were allowed to retrieve rewards from four arms of an eight-arm maze and then tested for reentry errors 8 hr later. The number of such errors was substantially reduced on days in which the animals were inJected with the drug before initial learning. These results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements. This may reflect an action on the cellular mechanisms responsible for producing synaptic changes since facilitation of AMPA receptors promotes the induction of the long-term potentiation effect.Recent work indicates that facilitation of DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (glutamate) receptor-mediated transmission in slices of hippocampus reduces the amount of afferent stimulation needed to induce a maximal degree of long-term potentiation (LTP) without changing the LTP "ceiling" itself (1). Because there is evidence implicating LTP as a substrate for certain types of memory (2), it is possible that drugs that produce such effects in brain will reduce the amount of training needed for the formation of robust memory. The experiments reported here tested this idea by using a drug that crosses the bloodbrain barrier and enhances synaptic responses in freely moving animals.The carbonic anhydrase inhibitor cyclothiazide and the nootropic compound aniracetam enhance excitatory transmission in vitro by prolonging the open time of glutamate (AMPA) receptors (3-6). Cyclothiazide probably does not cross the blood-brain barrier (7) and aniracetam is rapidly metabolized in peripheral tissues to anisoyl -y-aminobutyric acid (GABA) (8), which we have found to have little effect onThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "adv...

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

“…Manipulating glutamatergic receptors appear to affect LTP and memory. For instance, blocking glutamatergic transmission via an NMDA receptor antagonist causes LTP reduction and impaired learning (Davis et al,1992; Stäubli et al,1994). Therefore, the assumption of increased glutamatergic transmission would be in line with our finding regarding memory performance.…”

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

“…It is interesting to note that PPI deficit of mGluR5 À/À mice was consistently detected regardless of prepulse intensity effect; however, positive AMPAR modulator, CX546, improved PPI in prepulse intensity-dependent manner, implying that positive treatment can ameliorate the effect of intensity on sensorimotor gaiting processes. Originally aniracetam initiated development of more potent positive AMPAR modulators such as 'ampakines' that rapidly cross blood-brain barrier and facilitate synaptic transmission in the hippocampus (Granger et al, 1993;Staubli et al, 1994). Hence, known low potency and rapid metabolism of aniracetam (Lynch, 2004) can explain its mild effect on PPI deficit in mGluR5 mutants compared to the pronounced CX546 effect.…”

AMPA Receptor Facilitation Accelerates Fear Learning without Altering the Level of Conditioned Fear Acquired

“…Because the synaptic changes occurring during LTP induction have been widely hypothesized to be similar to those occurring during memory formation (Lynch, 1986;Brown et al, 1988;Teyler, 1992;Bliss and Collingridge, 1993;Barnes et al, 1995;Stäubli, 1995), the facilitating effects of ampakines on LTP have stimulated researchers to ask whether these drugs enhance the acquisition and storage of memories. Ampakines have now been shown to enhance retention in several tasks, including the radial arm maze (Granger et al, 1993;Stäubli et al, 1994aStäubli et al, ,b, 1996, water maze (Stäubli et al, 1994a), and olfactory delayed match to sample (Stäubli et al, 1994b(Stäubli et al, , 1996. Ampakines have also been found to render normally subthreshold stimulus parameters capable of supporting learning in odor discrimination (Stäubli et al, 1994a;Larson et al, 1995) and eyeblink conditioning (Shors et al, 1995) tasks.…”