NMDA receptors hippocampus

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

While there are some reports of increased NMDA and non-NMDA receptor number in various cortical regions of schizophrenics including the prefrontal cortex, there are also indications of impaired glutamate innervation, such as reduction in its neuronal uptake sites (Ishimaru, Kurumaji and Torn 1994). Also it has been found that levels of the mRNA for the NRI subunit of the NMDA receptor in the hippocampus and its D-aspartate binding sites in the temporal cortex are both reduced more on the left than right side in schizophrenic brain. This is another indication of greater malfunction on the left side of the brain and the possibility that some schizophrenic symptoms arise from an imbalance between cross-cortical activity. 

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]. 

FIGURE 15-7 Regional distribution of mRNAs encoding the five NMDA receptor genes in adult rat brain, by in situ hybridization. OB, olfactory bulb Cx, cortex Hi, hippocampus Cb, cerebellum Th, thalamus St, striatum. (With permission from Nakanishi, S. Science 258,597-603,1992.)... 

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... 

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... 

Davidson J, Lipper S, KUts CD, Mahorney S, Hammett E (1985) Platelet MAO activity in posttraumatic stress disorder. Am J Psychiatry 142 1341-1343 Davis M (2002) The role of NMDA receptors and MAP kinase in the amygdala in extinction of fear clinical implications for exposure therapy. Eur J Neurosci 16 395-398 DeBellis MD, Letter L, Trickett PK, Putnam FW (1994) Urinary catecholamine excretion in sexually abused girls. J Am Acad Child Adoles Psychiatry 33 320-327 Debiec J, LeDoux JE, Nader K (2002) Cellular and systems reconsolidation in the hippocampus. Neuron 36 527-538... 

It is striking that the behavioural consequences of an impairment of as GABAa receptors are opposite to those of a NMDA receptor deficit. While mice with a deficit in hippocampal NMDA receptors (NRI-CAl knockout) show a deficit in the formation of spatial and temporal memory (Tsien et al. 1996 Tang et al. 1999), the mice with a deficit in as GABAa receptors display an improvement in hippocampal spatial and temporal memory performance. Thus, it appears that these two receptor systems play a complementary role in controlling neuronal processing in the hippocampus. 

Physiological studies have identified both post- and presynaptic roles for ionotropic kainate receptors. Kainate receptors contribute to excitatory post-synaptic currents in many regions of the CNS including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are codistributed with AMPA and NMDA receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors for example, in the retina at connections made by cones onto off bipolar cells. Extrasynaptically located postsynaptic kainate receptors are most likely activated by spill-over glutamate (Eder et al. 2003). Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. The hyperexcitability evoked by locally applied kainate, which is quite effectively reduced by endocannabinoids, is probably mediated preferentially via an activation of postsynaptic kainate receptors (Marsicano et al. 2003). 

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