Learning

alpha-calmodulin kinase II (alphaCaMKII) [GE]
    A regulatable transgene coding for a mutant, activated alpha-calmodulin kinase II (alphaCaMKII) was introduced into mice.  The mutant gene was expressed only in the forebrain.  Mice expressing the mutant alpha-calmodulin kinase II showed impaired spatial learning, memory, and LTP.  Mayford et al., Science, 274:1678-1683, 1996.  See, also, Cho et al., Science, 279:867-869, 1998.

cAMP-responsive element binding protein (CREB) [GE]
    Mice deficient in the alpha and delta isoforms of the cAMP-responsive element binding protein (CREB) show reduced LTP and mild spatial learning deficits.  Cho et al., Science, 279:867-869, 1998.

corticotropin-releasing factor receptor, subtype 1 (CRFR1) [GE]
    Corticotropin-releasing factor receptor, subtype 1 (CRFR1)-deficient mice displayed increased exploratory behavior in the elevated Plus-Maze and the Black and White test box, both models of anxiety.  These results suggested that the CRFR1 gene plays a role in anxiety.  The CRFR1 deficient mice also were impaired in spatial recognition memory, indicating that this gene is involved in cognitive biological processes, as well.  Contarino et al., Brain Res., 835:1-9, 1999.

N-methyl-D-aspartate (NMDA) receptor 2B (NR2B) [GE]
    Genetic engineering of the NMDA receptor has produced a smart mouse.  NMDA receptors are multisubunit receptors comprising a subunit 1 (NR1) and a subunit 2 (NR2).  NR1 is essential for channel function.  NR2 is involved in the kinetics of channel function.  There are several types of NR2 subunits, including NR2A and NR2B. In vitro studies have suggested that NR2B is involved in synaptic plasticity and memory.  During the transition from fetal stage to adult, the NR2B receptor is down-regulated.  Transgenic mice were constructed which overexpressed NR2B postnatally in the mice forebrain.  Visual recognition memory in engineered mice was enhanced in comparison to wild-type controls.  Moreover, they learned faster than controls in two types of behavioral paradigms.  Tang et al., Nature, 401:63-69, 1999.

nerve growth factor (NGF) [GE]
    Mice were engineered with a silent nerve growth factor (NGF) gene containing an element (loxP) which could be activated by an inducer molecule (cre recombinase).  The inducer was introduced into the brain by intracerebral delivery of a viral vector containing the gene coding for the inducer molecule.  Introduction of the vector into the hippocampus of the brain of adult mice resulted in a 10-fold local increase in NGF.  This local increase in NGF expression augmented learning and memory in a learning paradigm that distinguished between increased motor function, sensory ability, and motivation.  Moreover, the augmentation was accompanied by an increase of cholinergic neurons in the basal forebrain, the region of the brain to which the hippocampus projects.  Brooks et al., Proc. Natl. Acad. Sci., 97:13378-13383, 2000.

postsynaptic density-95 protein (PSD-95) [GE]
    The postsynaptic density-95 protein (PSD-95) is localized to the post-synaptic membrane of neurons.  It contains several domains which participate in protein-protein interactions, including (from 5' to 3') three PDZ domains, a SH3 homology domain, and guanylate kinase homology region.  The second PDZ domain possesses the ability to bind to the NR2 subunit of the NMDA receptor.  Mutant mice were constructed by homologous recombination in which the normal gene was replaced by a copy of a PSD-95 gene mutation in which a stop codon had been introduced after the first two PDZ domains.  NMDA receptors localized normally to the post-synaptic region and synaptic transmission was normal, but LTP in hippocampal slices was abnormal in mutant mice.  Spatial learning was also impaired in mutant mice.  Migaud et al., Nature, 396:433-439, 1998.

thyroid hormone receptor, type beta-1 (TR-beta-1) [GE]
    Mice were engineered to express a mutant form of the beta-1 subtype of the thyroid hormone receptor (TR-beta-1).  Mutant mice exhibited impaired learning and elevated locomotor activity in an open field test.  These characteristics are analogous to behavior characteristics observed in attention deficit hyperactivity disorder (ADHD).  McDonald et al., Learn.  Mem., 5:289-301, 1998.