Memory NMDA receptor

Studies reveal that a homozygous GlyT-1 (-/-) knockout in mice is neonatally lethal. However heterozygous GlyT-1 (+/-) mice survive to adulthood and display enhanced NMDA receptor function in the hippocampus, better memory retention, and no disruption in sensory gating when dosed with amphetamine [15]. 

Tsien, I. Z., Huerta, P. T. and Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87 1327-1338,1996. 

Reports that AA is released primarily by G-protein-mediated PLA2 activation remain to be confirmed [84, 85]. In addition, modulation of PLA2 by Ca2+ and protein kinase needs to be better defined. It is clear that NMDA receptor activation promotes the release of AA [86], and that a variety of eicosanoids are then generated (Fig 33-2,33-3). The modulatory events that channel AA towards specific eicosanoids are not understood. The endocannabinoid family of lipid messengers will remain an active focus of interest because of the growing evidence of their actions in synaptic function, learning, memory, and other forms of behavior [56,87]. 

Initial evidence linking Hebb s coincidence detection rule to learning and memory. As the unique receptor in the brain with the coincidence-detection property, the NMDA receptor is an ideal candidate to gate the formation of memory at the synaptic level. Early observations demonstrated that infusion of NMDA receptor blockers into brain ventricles resulted in animals poor performance in the hidden-platform water maze. At first, this seemed to provide evidence for the role of hippocampal LTP in memory formation. Unfortunately, careful analyses revealed that poor performances in the water maze tests... 

While the conditional gene knockout experiments are supportive of a role for the NMDA receptors in memory, they are less than fully conclusive in linking the synaptic coincidence-detection feature of the NMDA receptor to memory formation. Like all loss-of-function studies, CA1-specific gene-knockout experiments could, in theory, produce memory impairment via a mechanism independent of the coincidence-detection function of the NMDA receptor. For example, one may argue that the physical absence of the NMDA receptor channels may cause subtle structural reconfiguration at the synapse, thereby altering normal synaptic transmission. Therefore, the memory impairment in CA1-specific NR1 knockout mice does not allow a firm conclusion that the coincidence-detection function of NMDA receptors controls learning and memory processes at the cellular level. 

Cui, Z. Z., Wang, H., Tan, Y. et al. Inducible and reversible NR1 knockout reveals crucial role of the NMDA receptor in preserving remote memories in the brain. Neuron 41 781-793, 2004. 

However, it is not the only mechanism, because drugs that do not work at NMDA receptors can impair memory (e.g., benzodiazepines). Other EAA receptors include the ionotropic AMPA and kainate receptors, and the metabotropic glutamate receptors (mGluR). 

It is a matter of debate whether memories can be erased at all (Jacobs and Nadel 1985). However, there is some evidence from animal experiments that processes that lead to learning or LTP-induced changes in interneuronal communication can be reversed by specific opponents of the consolidation cascade, as for instance phosphatases (Genoux et al. 2002 Lin et al. 2003a,b). The decay of both LTP and memory seems to depend on NMDA receptors. However, there are conflicting data as to whether recurrent activation of NMDA receptors promotes decay or long-term consolidation processes (Shimizu et al. 2000 Villarreal et al. 2002). 

Izquierdo I, Schroder N, Netto CA, Medina JH (1999) Novelty causes time-dependent retrograde amnesia for one-trial avoidance in rats through NMDA receptor- and CaMKII-dependent mechanisms in the hippocampus. Eur J Neurosci 11 3323-3328 Izquierdo LA, Barros DM, Vianna MR, Coitinho A, deDavid e Silva T, Choi H, Moletta B, Medina JH, Izquierdo I (2002) Molecular pharmacological dissection of short- and longterm memory. Cell Mol Neurobiol 22 269-287 Jacobs WJ, Nadel L (1985) Stress-induced recovery of fears and phobias. Psychol Rev 92 512-531... 

Shimizu E, Tang YP, Rampon C, Tsien JZ (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290 1170-1174 Shobe J (2002) The role of PKA, CaMKll, and PKC in avoidance conditioning permissive or instructive Neimobiol Learn Mem 77 291-312 Shimiyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111 905-918... 

Vanderwolf CH, Cain DP (1994) The behavioral neurobiology of learning and memory a conceptual reorientation. Brain Res Brain Res Rev 19 264-297 Villarreal DM, Do V, Haddad E, Derrick BE (2002) NMDA receptor antagonists sustain LTP and spatial memory active processes mediate LTP decay. Nat Neurosci 5 48-52 Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of d-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22 2343-2351 Wallenstein GV, Eichenbaum H, Hasselmo ME (1998) The hippocampus as an associator of discontiguous events. Trends Neurosci 21 317-323 Wehner JM, Radcliffe RA, Bowers BJ (2001) Quantitative genetics and mouse behavior. Annu Rev Neurosci 24 845-867... 

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