ATM protein is located on presynaptic vesicles and its deficit leads to failures in synaptic plasticity.

Ataxia telangiectasia is a multisystemic disorder that includes a devastating neurodegeneration phenotype. The ATM (ataxia-telangiectasia mutated) protein is well-known for its role in the DNA damage response, yet ATM is also found in association with cytoplasmic vesicular structures: endosomes and lysosomes, as well as neuronal synaptic vesicles. In keeping with this latter association, electrical stimulation of the Schaffer collateral pathway in hippocampal slices from ATM-deficient mice does not elicit normal long-term potentiation (LTP). The current study was undertaken to assess the nature of this deficit. Theta burst-induced LTP was reduced in Atm(-/-) animals, with the reduction most pronounced at burst stimuli that included 6 or greater trains. To assess whether the deficit was associated with a pre- or postsynaptic failure, we analyzed paired-pulse facilitation and found that it too was significantly reduced in Atm(-/-) mice. This indicates a deficit in presynaptic function. As further evidence that these synaptic effects of ATM deficiency were presynaptic, we used stochastic optical reconstruction microscopy. Three-dimensional reconstruction revealed that ATM is significantly more closely associated with Piccolo (a presynaptic marker) than with Homer1 (a postsynaptic marker). These results underline how, in addition to its nuclear functions, ATM plays an important functional role in the neuronal synapse where it participates in the regulation of presynaptic vesicle physiology.

Individual differences in the expression of a "general" learning ability in mice.

Human performance on diverse tests of intellect are impacted by a "general" regulatory factor that accounts for up to 50% of the variance between individuals on intelligence tests. Neurobiological determinants of general cognitive abilities are essentially unknown, owing in part to the paucity of animal research wherein neurobiological analyses are possible. We report a methodology with which we have assessed individual differences in the general learning abilities of laboratory mice. Abilities of mice on tests of associative fear conditioning, operant avoidance, path integration, discrimination, and spatial navigation were assessed. Tasks were designed so that each made unique sensory, motor, motivational, and information processing demands on the animals. A sample of 56 genetically diverse outbred mice (CD-1) was used to assess individuals' acquisition on each task. Indicative of a common source of variance, positive correlations were found between individuals' performance on all tasks. When tested on multiple test batteries, the overall performance ranks of individuals were found to be highly reliable and were "normally" distributed. Factor analysis of learning performance variables determined that a single factor accounted for 38% of the total variance across animals. Animals' levels of native activity and body weights accounted for little of the variability in learning, although animals' propensity for exploration loaded strongly (and was positively correlated) with learning abilities. These results indicate that diverse learning abilities of laboratory mice are influenced by a common source of variance and, moreover, that the general learning abilities of individual mice can be specified relative to a sample of peers.

Exploration in outbred mice covaries with general learning abilities irrespective of stress reactivity, emotionality, and physical attributes.

Across multiple learning tasks (that place different sensory, motor, and information processing demands on the animals), we have found that the performance of mice is commonly regulated by a single factor ("general learning") that accounts for 30-40% of the variance across individuals and tasks. Furthermore, individuals' general learning abilities were highly correlated with their propensity to engage in exploration in an open field, a behavior that is potentially stress-inducing. This relationship between exploration in the open field and general learning abilities suggests the possibility that variations in stress sensitivity/responsivity or related emotional responses might directly influence individuals' general learning abilities. Here, the relationship of sensory/motor skills and stress sensitivity/emotionality to animals' general learning abilities were assessed. Outbred (CD-1) mice were tested in a battery of six learning tasks as well as 21 tests of exploratory behavior, sensory/motor function and fitness, emotionality, and stress reactivity. The performances of individual mice were correlated across six learning tasks, and the performance measures of all learning tasks loaded heavily on a single factor (principal component analysis), accounting for 32% of the variability between animals and tasks. Open field exploration and seven additional exploratory behaviors (including those exhibited in an elevated plus maze) also loaded heavily on this same factor, although general activity, sensory/motor responses, physical characteristics, and direct measures of fear did not. In a separate experiment, serum corticosterone levels of mice were elevated in response to a mild environmental stressor (confinement on an elevated platform). Stress-induced corticosterone levels were correlated with behavioral fear responses, but were unsystematically related to individuals' propensity for exploration. In total, these results suggest that although general learning abilities are strongly related to individuals' propensity for exploration, this relationship is not attributable to variations in sensory/motor function or the individuals' physiological or behavioral sensitivity to conditions that promote stress or fear.