Role of hippocampal NMDA receptors in trace eyeblink conditioning

We examined the effects of acute injections of competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) into the dorsal hippocampus on contextual fear conditioning and classical eyeblink conditioning in C57BL/6 mice. When injected 10 to 40 min before training, APV severely impaired contextual fear conditioning. Thus, APV injection under these conditions was sufficient to suppress hippocampal NMDA receptors. To investigate the role of hippocampal NMDA receptors on eyeblink conditioning, we carried out daily training of mice during 10-40 min after injection of APV. In the delay eyeblink conditioning, in which the unconditioned stimulus (US) is delayed and terminates simultaneously with the conditioned stimulus (CS), APV-injected mice acquired the conditioned responses (CRs) as well as artificial cerebrospinal fluid (aCSF)-injected control mice did. However, in the trace eyeblink conditioning, in which the CS and US were separated by a stimulus-free trace interval of 500 ms, APV-injected mice showed severe impairment in acquisition of the CR. There was no significant difference in pseudo-conditioning between APV- and aCSF-injected mice. These results provide evidence that the NMDA receptor in the dorsal hippocampus is critically involved in acquisition of the CR in long trace eyeblink conditioning.

[1]  M. Wilson,et al.  Formation of Temporal Memory Requires NMDA Receptors within CA1 Pyramidal Neurons , 2000, Neuron.

[2]  Richard E Thompson,et al.  Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning , 1997, Trends in Neurosciences.

[3]  M. Mishina.  Timing determines the neural substrates for eyeblink conditioning , 2003 .

[4]  R. F. Thompson,et al.  Hippocampus and trace conditioning of the rabbit's classically conditioned nictitating membrane response. , 1986, Behavioral neuroscience.

[5]  Yutaka Kirino,et al.  Time-Dependent Reorganization of the Brain Components Underlying Memory Retention in Trace Eyeblink Conditioning , 2003, The Journal of Neuroscience.

[6]  Richard F. Thompson,et al.  Neural substrates of eyeblink conditioning: acquisition and retention. , 2003, Learning & memory.

[7]  J. Steinmetz,et al.  Intra-cerebellar infusion of NMDA receptor antagonist AP5 disrupts classical eyeblink conditioning in rabbits , 2000, Brain Research.

[8]  R. Morris,et al.  The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  S. Kotani,et al.  The Hippocampus Plays an Important Role in Eyeblink Conditioning with a Short Trace Interval in Glutamate Receptor Subunit δ2 Mutant Mice , 2003, The Journal of Neuroscience.

[10]  David G. Lavond,et al.  Trace conditioning: Abolished by cerebellar nuclear lesions but not lateral cerebellar cortex aspirations , 1985, Brain Research.

[11]  S Kawahara,et al.  Classical eyeblink conditioning in glutamate receptor subunit δ2 mutant mice is impaired in the delay paradigm but not in the trace paradigm , 2001, The European journal of neuroscience.

[12]  T. Manabe,et al.  Increased Thresholds for Long-Term Potentiation and Contextual Learning in Mice Lacking the NMDA-type Glutamate Receptor ε1 Subunit , 1998, The Journal of Neuroscience.

[13]  S. Kawahara,et al.  Long‐trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit ε1 , 2001 .

[14]  S. Wang,et al.  Coincidence detection in single dendritic spines mediated by calcium release , 2000, Nature Neuroscience.

[15]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[16]  T. Shors,et al.  Early acquisition, but not retention, of the classically conditioned eyeblink response is N-methyl-D-aspartate (NMDA) receptor dependent. , 1996, Behavioral neuroscience.

[17]  I. Daum,et al.  The NMDA antagonist memantine impairs classical eyeblink conditioning in humans , 1997, Neuroscience Letters.

[18]  O. Stiedl,et al.  Impairment of conditioned contextual fear of C57BL/6J mice by intracerebral injections of the NMDA receptor antagonist APV , 2000, Behavioural Brain Research.

[19]  S. Kawahara,et al.  Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice , 2001, Neuropharmacology.

[20]  J. Disterhoft,et al.  Cortical involvement in acquisition and extinction of trace eyeblink conditioning. , 2000, Behavioral neuroscience.

[21]  John F. Disterhoft,et al.  Lesions of the Caudal Area of Rabbit Medial Prefrontal Cortex Impair Trace Eyeblink Conditioning , 1998, Neurobiology of Learning and Memory.

[22]  G. B. Robinson.  MK801 retards acquisition of a classically conditioned response without affecting conditioning-related alterations in perforant path-granule cell synaptic transmission , 1993, Psychobiology.

[23]  M. Fanselow,et al.  N-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning. , 1991, Behavioral neuroscience.

[24]  Joseph E LeDoux,et al.  Parallels between cerebellum- and amygdala-dependent conditioning , 2002, Nature Reviews Neuroscience.

[25]  J. Green,et al.  Eyeblink classical conditioning: hippocampal formation is for neutral stimulus associations as cerebellum is for association-response. , 2000, Psychological bulletin.

[26]  Tracey J. Shors,et al.  Associative Memory Formation Increases the Observation of Dendritic Spines in the Hippocampus , 2003, The Journal of Neuroscience.

[27]  S. Kawahara,et al.  Impairment of eyeblink conditioning in GluRδ2‐mutant mice depends on the temporal overlap between conditioned and unconditioned stimuli , 2001, The European journal of neuroscience.

[28]  J. Disterhoft,et al.  Trace eyeblink conditioning is hippocampally dependent in mice , 2004, Hippocampus.

[29]  Lucien T. Thompson,et al.  N-methyl-D-aspartate receptors in associative eyeblink conditioning: both MK-801 and phencyclidine produce task- and dose-dependent impairments. , 1997, The Journal of pharmacology and experimental therapeutics.