Showing papers by "Susumu Tonegawa published in 2009"

CA3 NMDA receptors are required for the rapid formation of a salient contextual representation.

Abstract: The acquisition of Pavlovian fear learning engages the hippocampus when the conditioned stimuli are multimodal or temporally isolated from the unconditioned stimuli. By subjecting CA3-NR1 KO mice to conditioning protocols that incorporate time-dependent components, we found that the loss of plasticity at recurrent CA3 synapses resulted in a deficits in contextual conditioning specifically when the exposure to the context was brief or when the unconditioned stimulus was signaled with a competing, predictive unimodal stimulus. Our results suggest CA3 contributes both speed and salience to contextual processing and support the theory of competition between multimodal and unimodal conditioned stimuli for associative learning.

Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death.

Abstract: Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-D-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave-ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced gamma-aminobutyric acid (GABA) levels, and the persistent 30-50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker alpha-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy.

RAPID COMMUNICATION CA3 NMDA Receptors Are Required for the Rapid Formation of a Salient Contextual Representation

Abstract: The acquisition of Pavlovian fear learning engages the hippocampus when the conditioned stimuli are multimodal or tempo- rally isolated from the unconditioned stimuli. By subjecting CA3-NR1 KO mice to conditioning protocols that incorporate time-dependent components, we found that the loss of plasticity at recurrent CA3 synap- ses resulted in a deficits in contextual conditioning specifically when the exposure to the context was brief or when the unconditioned stimu- lus was signaled with a competing, predictive unimodal stimulus. Our results suggest CA3 contributes both speed and salience to contextual processing and support the theory of competition between multimodal and unimodal conditioned stimuli for associative learning. V C 2009 Wiley-