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
The identification of the genetic determinants specifying neuronal networks in the mammalian brain is crucial for the understanding of the molecular and cellular mechanisms that ultimately control cognitive functions. Here we have generated a targeted allele of the LIM-homeodomain-encoding gene Lhx7 by replacing exons 3-5 with a LacZ reporter. In heterozygous animals, which are healthy, fertile and have no apparent cellular deficit in the forebrain, b-galactosidase activity reproduces the pattern of expression of the wild-type Lhx7 locus. However, homozygous mutant mice show severe deficits in forebrain cholinergic neurons (FCNs), while other classes of forebrain neurons appear unaffected. Using the LacZ reporter as a marker, we show that in LHX7-deficient mice FCN progenitors survive but fail to generate cholinergic interneurons in the striatum and cholinergic projection neurons in the basal forebrain. Analysis of behaviour in a series of spatial and non-spatial learning and memory tasks revealed that FCN ablation in Lhx7 mutants is associated with severe deficits in spatial but only mild impairment of non-spatial learning and memory. In addition, we found no deficit in long-term potentiation in mutant animals, suggesting that FCNs modulate hippocampal function independently of its capacity to store information. Overall our experiments demonstrate that Lhx7 expression is required for the specification or differentiation of cholinergic forebrain neurons involved in the processing of spatial information.
Subject(s)
Basal Nucleus of Meynert/abnormalities , Basal Nucleus of Meynert/metabolism , Cholinergic Fibers/metabolism , Homeodomain Proteins/genetics , Learning Disabilities/metabolism , Memory Disorders/metabolism , Prosencephalon/metabolism , Acetylcholine/metabolism , Animals , Basal Nucleus of Meynert/pathology , Cell Death/genetics , Cell Differentiation/genetics , Cholinergic Fibers/pathology , Corpus Striatum/abnormalities , Corpus Striatum/metabolism , Corpus Striatum/pathology , Dentate Gyrus/metabolism , Dentate Gyrus/physiopathology , Disease Models, Animal , Genes, Reporter/genetics , Homeodomain Proteins/metabolism , Interneurons/metabolism , Interneurons/pathology , LIM-Homeodomain Proteins , Lac Operon/genetics , Learning Disabilities/genetics , Learning Disabilities/physiopathology , Long-Term Potentiation/genetics , Male , Memory Disorders/genetics , Memory Disorders/physiopathology , Mice , Mice, Knockout , Nervous System Malformations/genetics , Nervous System Malformations/metabolism , Nervous System Malformations/physiopathology , Prosencephalon/physiopathology , Transcription FactorsABSTRACT
We have investigated synaptic function in the hippocampus in mice of different ages carrying a null mutation in the PrP gene. Experiments carried out in vivo and in vitro in two laboratories revealed no differences in the ability of juvenile and young adult control and PrP-null mice to express long-term potentiation, paired-pulse facilitation, or posttetanic potentiation in either the dentate gyrus or in the CA1 region. However, we found a significant reduction in the level of posttetanic potentiation and long-term potentiation in the CA1 region of aged PrP-null mice. These results are discussed in relationship to reported increased levels of oxidative stress in older PrP-null mice.
Subject(s)
Hippocampus/physiology , Long-Term Potentiation/physiology , Prions/genetics , Age Factors , Analysis of Variance , Animals , Electric Stimulation/methods , Electrodes, Implanted , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Long-Term Potentiation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Regression AnalysisABSTRACT
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.
