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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.06.038 Byline: Kuan Hong Wang (1)(2)(3)(4)(5), Ania Majewska (2)(5), James Schummers (2)(5), Brandon Farley (2)(5), Chengcheng Hu (6), Mriganka Sur (2)(5), Susumu Tonegawa (1)(2)(3)(4)(5) Abstract: Cortical representations of visual information are modified by an animal's visual experience. To investigate the mechanisms in mice, we replaced the coding part of the neural activity-regulated immediate early gene Arc with a GFP gene and repeatedly monitored visual experience-induced GFP expression in adult primary visual cortex by in vivo two-photon microscopy. In Arc-positive GFP heterozygous mice, the pattern of GFP-positive cells exhibited orientation specificity. Daily presentations of the same stimulus led to the reactivation of a progressively smaller population with greater reactivation reliability. This adaptation process was not affected by the lack of Arc in GFP homozygous mice. However, the number of GFP-positive cells with low orientation specificity was greater, and the average spike tuning curve was broader in the adult homozygous compared to heterozygous or wild-type mice. These results suggest a physiological function of Arc in enhancing the overall orientation specificity of visual cortical neurons during the post-eye-opening life of an animal. Author Affiliation: (1) Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA (2) The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA (3) RIKEN-MIT Neuroscience Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA (4) Department of Biology and Massachusetts Institute of Technology, Cambridge, MA 02139, USA (5) Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA (6) Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA Article History: Received 31 August 2005; Revised 16 January 2006; Accepted 5 June 2006 Article Note: (miscellaneous) Published: July 27, 2006

Results point out that the calcium-dependent protein phosphatase, calcineurin, of the mouse forebrain mediates the bidirectional synaptic plasticity and differentiates between working/episodic-like memory and reference memory. Mutant mice with disrupted calcineurin show impairment in hippocampus-dependent working and episodic-like memory tasks.

Research has been conducted on the calcium/calmodulin-dependent protein kinase IV. The role of this kinase in the neuronal plasticity and memory has been investigated via the generated transgenic mice with the dominant-negative calcium/calmodulin-dependent protein kinase IV form expression restricted to the postnatal forebrain and the results are presented.

Brain-derived neurotrophic factor (BDNF), which regulates maturation of inhibition and the critical period of plasticity in the visual cortex of mice, is discussed. Visual cortex maturation is influenced by visual experience during an early postnatal period. In transgenic mice in which the postnatal increase of BDNF was speeded up, this was studied. Maturation of GABAergic innervation and inhibition was speeded up and the age-dependent decline of cortical long-term potentiation induced by white matter stimulation happened sooner. Precocious development of visual acuity and an earlier end for the critical period for ocular dominance plasticity was seen.

The normal physiological role of the Presenilin-1 (PS1) was analyzed in PS1 homozygous mutant mice. Homozygous mutations in the PS1 gene in mice that were derived from four independent embryonic stem cell lines induced death after natural birth or caesarean-section. The PS1 homozygous mutant mice also exhibited gross skeletal and central nervous system abnormalities . Furthermore, brain abnormalities in the mutants was caused by reduced number of progenitor cells and neurons in the ventrolateral region of the ventricular zone.

A cell-type restricted gene knockout technology for mice was developed based on the phage P1-derived Cre/loxP recombination-based gene deletion system. The forebrain restricted gene knockout technology involves the production of Cre transgenic mice by Cre/loxP recombination is dependent on the nature of the transcription promoter that regulates Cre gene expression. The floxed stop and lacZ sequences were also utilized to determine the subregional specificity of Cre/lox recombination.

A novel method based on the Cre/loc recombination system from phage P1 was utilized for the restricted deletion of the (N-methyl-D-aspartate receptor) NMDAR1 gene in the pyramidal cells of the hippocampal CA1 region of mice. The CA1-restricted NMDAR1 mutants developed normal brains but the slow component of the excitatory postsynaptic current was absent in their CA1-knock out cells. Furthermore, the mutant mice exhibited deficient learning abilities and spatial memory indicating the role of NMDA in the formation of specific forms of memory.

The hippocampal activity of mutant mice exhibiting CA1 restricted deletion of the N-methyl-D-aspartate receptor subunit 1 (NMDAR1) gene was analyzed by utilizing multielectrode recording techniques. The CA1 restricted NMDAR1 mutants exhibited normal neuronal firing activity characterized by rhythmic modulations of the firing rate with a theta frequency of 8-10 Hertz. However, the NMDAR1 mutants exhibited deficient neuronal firing during the performance of spatial tasks indicating the role of NMDAR1 in spatial memory and synaptic plasticity.

Mutant mice deficient in protein kinase C-gamma are unable to coordinate motor activity but learn discrete motion elements such as eyeblinking conditioning. Cerebellar long-term depression is unaffected in the mutants.The motor coordination defects are probably due to the presence of excess multiple climbing fibers in the Purkinje cells of the mutants.

Protein kinase C-gamma (PKC-gamma) may function as a downstream element in eliminating excess climbing fiber (CF) synapses. Adult mutant mice lacking PKC-gamma show multiple CFs in 41% of the Purkinje cells (PCs) unlike the wild-type mice whose PCs have single CF innervation. The mutants have a normal anatomy and normal transmission of excitatory stimuli in CF-PC and the parallel fiber-PC synapses. The mutants show normal regression of multiple CF innervation until two weeks after birth followed by a reduction in regression.

A study of the involvement of the dopamine D1 receptor in cocaine-induced hyperactivity using gene targeting-produced dopamine receptor mutant mice reveals a decrease in locomotion in the mutant mice that is dose-dependent. Electrophysiological studies reveal the complete elimination of the cocaine-induced inhibition of the production of action potentials by the dopamine-sensitive nucleus accumbens neurons. The mutant mice do not possess dopamine and D1 and D2 agonist inhibitory effects but retain the inhibitory effects of serotonin. The mice also exhibit normal D2-like dopamine receptor binding.

Histological studies to determine the function of brain dopamine D1 receptor in D1 receptor mutant mice reveals that the D1 receptor is vital for normal motor activity levels and modulates the neurochemical structure of the striatum. The mutant mice display a decrease in dymorphin expression in the basal ganglia and striatum but do not display significant changes in the anatomy of the brain. D1 receptor antagonists and agonists fail to trigger the mutant mice that also display locomotor hyperactivity.

mGLuR1-absent mice exhibit ataxic cerebellar symptoms and defective long term depression (LTD) and conditioned eyeblink response. They exhibit normal cerebellar anatomy, functional excitatory synaptic transmission from parallel and climbing fibers to the Purkinje cells and normal voltage-gated Ca+ channels of Purkinje cells. Observations on the mutant mice suggest that LTD activation requires mGLuR1 and that LTD deficiency leads to defective eyeblinking and ataxic symptoms.

The generation of a new strain of mutant mice with a deletion in the gene that encodes metabotropic glutamate receptor 1 enables the study of its involvement in learning and memory through its role in synaptic plasticity and transmission. The mutant exhibits deficiency in context-specific associative learning and diminished long term potentiation, despite normal levels of short term potentiation, normal hippocampal anatomy and synaptic transmission.

Activated myelin basic protein (MBP)-specific T lymphocytes occur in the brain of T cell receptor (TCR) non-transgenic (T/R-) and transgenic (T/R+) mice suffering from autoimmune encephalomyelitis (EAE). In the absence of other lymphocytes, MBP-specific CD4 T cells regulate EAE development. Nontransgenic lymphocytes offer protection against spontaneous EAE, although both T/R- and T/R+ mice have significantly encephalitogenic CD4 T cells. There is 100% susceptibility to EAE in mice expressing transgenic TCR.

The specificity of TCR-MHC interaction during positive selection is decided by the recognition of peptides by TCRs. The number of TCRs involved in peptide-MHC complexes is decided by the avidity between the two cell surface components, which in turn decides the fate of thymocytes. Moderate number of TCR leads to positive selection, while a high number results in negative selection.

Genomic Southern blot analysis of muted mice resulting from gene targeting of NMDAR1 subunit of N-methyl-D-aspartate (NMDA) revealed that while targeting and topographic projection of trigeminal afferents and postsynaptic neuron response to stimulation were normal, whisker-specific patterns did not appear due to the absence of NMDA receptors. The NMDA receptor influenced periphenyl-related neural patterns in mammals.

PKC-gamma mutant mice, characterized by modified long-term potentiation (LTP) of synaptic transmission on the hippocampus, exhibit corresponding deficits in spatial and contextual learning behavior. Disruption of long-term depression may also cause deficits in learning behavior. Presence of hippocampal CA1 LTP, resulting from tetanic stimulator, is not a prerequisite for spatial and contextual learning.

Mutant mice with a history of low frequency stimulation express long-term potentiation (LTP) without the actual production of long-term depression (LTD). This shows that PKC gamma is involved in the regulation of LTP but is not essential for the actual process of synaptic plasticity. The use history of a synapse probably modifies the state of the LTP regulatory systems in ways that are yet to be fully explained.

Mutant mice deficient in gamma-delta T cell receptor (TCR) were generated to elucidate the molecular mechanisms of the expression of distinct subsets of gamma-delta T cells. The results showed that differential generation of gamma-delta T cell subsets involves an intracellular mechanism acting at the DNA rearrangement level. Furthermore, gamma-delta T cells are not required for the normal development of alpha-beta T cells.

The coding part of the neural activity-regulated immediate gene Arc was replaced with a GFP gene in mice in order to investigate cortical representations of visual information which are modified by an animal's visual experience. The visual experience was repeatedly monitored by in vivo two-photon microscopy which showed a physiological function of Arc in enhancing the overall orientation specificity of visual cortical neurons during post-eye-opening life of an animal.

Using a pCRI plasmid containing an enzymatically synthesized, full-length DNA transcript of immunoglobulin λ chain mRNA as the hybridization probe in the Southern gel blotting experiments (Southern, 1975), we identified three DNA fragments of 8.6, 4.8 and 3.5 kb in Eco RI-digested total DNA from BLAB/c mouse embryos. A fourth fragment of 7.4 kb was found in addition to these three fragments in similarly digested total DNA from a λ chain-secreting myeloma (HOPC 2020). We have cloned the four DNA fragments in an EK- 2 phage vector, λWES, and characterized them with respect to size, type of λ gene sequences contained and position of these sequences in the fragments, using agarose gel electrophoresis, the gel blotting technique and electron microscopic R loop mapping. The embryonic DNA clones Ig 99λ, Ig 25λ and Ig 13λ contain one copy each of VλIs, CλI and VλII sequences, respectively, while the myeloma DNA clone Ig 303λ contains one copy each of VλI and CλIM sequences that are separated by a 1.2 kb nontranslated DNA segment. Ig 25λ was also shown to contain a DNA segment of approximately 40 base pairs (bp) (J sequence) that lies 1.2 kb away from the CλI sequence and is homologous to the V-C junction region of a λI mRNA. Heteroduplex analysis of the three A, DNA clones revealed that Ig 303λ DNA is composed of two parts, one of which is entirely homologous to one end of Ig 99λ, and the other to one end of Ig 25λ DNA. The sequence arrangement observed in the cloned DNA is the same as that in the corresponding cellular DNA. This was shown by identifying certain restriction enzyme cleavage sites on the cloned DNAs and demon- strating the presence of these sites in the total cellular DNA by the gel blotting technique. The site of the homology switch is at the boundary of the V sequence and the 1.2 kb nontranslated DNA segment, and corresponds to the position of the J sequence on the lg 25λ DNA. We consider the above experimental results the most direct evidence for somatic rearrangement in immunoglobulin genes. We discuss the significance of these findings for the origin of genes in the evolution of higher organisms and in cell differentiation. [ABSTRACT FROM AUTHOR]