The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome

Down's syndrome (DS) is the most common cause of mental retardation, and memory impairments are more severe in DS than in most if not all other causes of mental retardation. The Ts65Dn mouse, a genetic model of DS, exhibits phenotypes of DS, including memory impairments indicative of hippocampal dysfunction. We examined functional synaptic connectivity in area CA3 of the hippocampus of Ts65Dn mice using organotypic slice cultures as a model. We found reductions in multiple measures of synaptic function in both excitatory and inhibitory inputs to pyramidal neurons in CA3 of the Ts65Dn hippocampus. However, associational synaptic connections between pyramidal neurons were more abundant and more likely to be active rather than silent in the Ts65Dn hippocampus. Synaptic potentiation was normal in these associational connections. Decreased overall functional synaptic input onto pyramidal neurons expressed along with the specific hyperconnectivity of associational connections between pyramidal neurons will result in predictable alterations of CA3 network function, which may contribute to the memory impairments seen in DS.

[1]  A. M. Insausti,et al.  Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of down syndrome , 1998, Neuroscience Letters.

[2]  M. Davisson,et al.  Quantitative PCR genotyping assay for the Ts65Dn mouse model of Down syndrome. , 2003, BioTechniques.

[3]  A. Treves,et al.  Distinct Ensemble Codes in Hippocampal Areas CA3 and CA1 , 2004, Science.

[4]  M T Davisson,et al.  Segmental trisomy as a mouse model for Down syndrome. , 1993, Progress in clinical and biological research.

[5]  Stefano Vicari,et al.  Implicit and explicit memory: a functional dissociation in persons with Down syndrome , 2000, Neuropsychologia.

[6]  H. Lorenzi,et al.  Hippocampal hypocellularity in the Ts65Dn mouse originates early in development , 2006, Brain Research.

[7]  Alberto C. S. Costa,et al.  Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: A model of Down syndrome , 2005, Neuroscience Letters.

[8]  J. Knierim,et al.  Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3 , 2004, Nature.

[9]  Mara Dierssen,et al.  Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome , 2004, Brain Research.

[10]  Pico Caroni,et al.  Long-Term Rearrangements of Hippocampal Mossy Fiber Terminal Connectivity in the Adult Regulated by Experience , 2006, Neuron.

[11]  K M Harris,et al.  Three‐dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus , 1992, The Journal of comparative neurology.

[12]  L. Nadel,et al.  The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. , 2003, Child development.

[13]  L. Hyde,et al.  Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function , 2001, Behavioural Brain Research.

[14]  D Marr,et al.  Simple memory: a theory for archicortex. , 1971, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[15]  P. Yarowsky,et al.  Spatial memory deficits in segmental trisomic Ts65Dn mice , 1996, Behavioural Brain Research.

[16]  D. Muller,et al.  A simple method for organotypic cultures of nervous tissue , 1991, Journal of Neuroscience Methods.

[17]  C. Stafstrom,et al.  Epilepsy in Down syndrome: clinical aspects and possible mechanisms. , 1993, American journal of mental retardation : AJMR.

[18]  C. Jarrold,et al.  Impaired verbal short-term memory in Down syndrome reflects a capacity limitation rather than atypically rapid forgetting. , 2005, Journal of experimental child psychology.

[19]  R. Malenka,et al.  Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome , 2004, The Journal of Neuroscience.

[20]  D. Muller,et al.  Time course of synaptic development in hippocampal organotypic cultures. , 1993, Brain research. Developmental brain research.

[21]  J. Guzowski,et al.  Differences in Hippocampal Neuronal Population Responses to Modifications of an Environmental Context: Evidence for Distinct, Yet Complementary, Functions of CA3 and CA1 Ensembles , 2004, The Journal of Neuroscience.

[22]  B. Gähwiler,et al.  Excitatory synaptic transmission and its modulation by PKC is unchanged in the hippocampus of GAP‐43‐ deficient mice , 1999, The European journal of neuroscience.

[23]  A. R. Gardner-Medwin The recall of events through the learning of associations between their parts , 1976, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[24]  E. Rolls,et al.  Neural networks and brain function , 1998 .

[25]  H. Shinozaki,et al.  Activation of metabotropic glutamate receptor type 2/3 suppresses transmission at rat hippocampal mossy fibre synapses. , 1996, The Journal of physiology.

[26]  E. Niebuhr,et al.  Down's syndrome , 1974, Humangenetik.

[27]  P. Pavlidis,et al.  Pair Recordings Reveal All-Silent Synaptic Connections and the Postsynaptic Expression of Long-Term Potentiation , 2001, Neuron.

[28]  C. Epstein,et al.  Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome , 2004, The Journal of comparative neurology.

[29]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[30]  D. Debanne,et al.  Organotypic slice cultures: a technique has come of age , 1997, Trends in Neurosciences.

[31]  P. Pavlidis,et al.  Synaptic transmission in pair recordings from CA3 pyramidal cells in organotypic culture. , 1999, Journal of neurophysiology.

[32]  Z. Galdzicki,et al.  Understanding mental retardation in Down's syndrome using trisomy 16 mouse models , 2003, Genes, brain, and behavior.

[33]  C. Epstein,et al.  Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome , 1999, Neuropharmacology.

[34]  Jérôme Lejeune,et al.  Etude des chromosomes somatiques de neuf enfants mongoliens. , 1959 .

[35]  Max R. Bennett,et al.  Dynamics of the CA3 pyramidal neuron autoassociative memory network in the hippocampus. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[36]  S. Rapoport,et al.  Altered long-term potentiation in the young and old Ts65Dn mouse, a model for down syndrome , 1997, Neuropharmacology.

[37]  S. Pueschel,et al.  Seizure disorders in Down syndrome. , 1991, Archives of neurology.

[38]  R. Miles,et al.  Dual modulation of synaptic inhibition by distinct metabotropic glutamate receptors in the rat hippocampus. , 1995, The Journal of physiology.

[39]  James J. Knierim,et al.  Ensemble Dynamics of Hippocampal Regions CA3 and CA1 , 2004, Neuron.

[40]  H. Shinozaki,et al.  DCG-IV, a potent metabotropic glutamate receptor agonist, as an NMDA receptor agonist in the rat cortical slice , 1997, Brain Research.

[41]  D. Delis,et al.  Mechanisms of verbal memory impairment in four neurodevelopmental disorders , 2004, Brain and Language.