ABSTRACT
Arc/Arg3.1 is robustly induced by plasticity-producing stimulation and specifically targeted to stimulated synaptic areas. To investigate the role of Arc/Arg3.1 in synaptic plasticity and learning and memory, we generated Arc/Arg3.1 knockout mice. These animals fail to form long-lasting memories for implicit and explicit learning tasks, despite intact short-term memory. Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. In addition, long-term depression is significantly impaired. Together, these results demonstrate a critical role for Arc/Arg3.1 in the consolidation of enduring synaptic plasticity and memory storage.
Subject(s)
Cytoskeletal Proteins/physiology , Memory/physiology , Nerve Tissue Proteins/physiology , Neuronal Plasticity/physiology , Synapses/physiology , Analysis of Variance , Animals , Avoidance Learning/physiology , Behavior, Animal , Blotting, Southern/methods , Blotting, Western/methods , Conditioning, Classical/physiology , Cytoskeletal Proteins/deficiency , Dose-Response Relationship, Radiation , Electric Stimulation/methods , Excitatory Postsynaptic Potentials/genetics , Excitatory Postsynaptic Potentials/physiology , Hippocampus/cytology , In Vitro Techniques , Kainic Acid , Male , Maze Learning/physiology , Mice , Mice, Knockout , Nerve Tissue Proteins/deficiency , Neuronal Plasticity/genetics , Neurons/physiology , Patch-Clamp Techniques/methods , Seizures/chemically induced , Seizures/metabolism , Spatial Behavior/physiology , Synapses/genetics , Time FactorsABSTRACT
Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This "transchromosomic" mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools for dissecting other human aneuploidies.
Subject(s)
Aneuploidy , Chromosomes, Human, Pair 21 , Disease Models, Animal , Down Syndrome , Genetic Engineering , Mice, Transgenic , Animals , Behavior, Animal , Brain/pathology , Cell Count , Cell Line , Chimera , Down Syndrome/genetics , Down Syndrome/physiopathology , Embryo, Mammalian/cytology , Facial Bones/pathology , Female , Gene Expression , Genetic Markers , Heart Defects, Congenital/embryology , Hippocampus/physiopathology , Humans , Long-Term Potentiation , Lymphocyte Activation , Male , Maze Learning , Memory , Mice , Mice, Inbred Strains , Neurons/cytology , Oligonucleotide Array Sequence Analysis , Phenotype , Skull/pathology , Stem Cells , Synaptic Transmission , T-Lymphocytes/immunologyABSTRACT
Spatial learning of transgenic mice is often assessed in the Morris watermaze, where mice must use distant cues to locate a submerged platform. Such learning is confounded by species-specific noncognitive swimming strategies. Factor analysis permits cognitive and noncognitive strategies to be disentangled and their association with electrophysiological phenomena to be investigated.
