Hypofunction of N-methyl-D-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes-from molecular and physiological to behavioral-resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults-including excitotoxicity and oxidative stress-might help to explain their significant contribution to the development of schizophrenia.
A single factor (i.e., general intelligence) can account for much of an individuals' performance across a wide variety of cognitive tests. However, despite this factor's robustness, the underlying process is still a matter of debate. To address this question, we developed a novel battery of learning tasks to assess the general learning abilities (GLAs) of mice. Using this battery, we previously reported a strong relationship between GLA and a task designed to tax working memory capacity (i.e., resistance to competing demands). Here we further explored this relationship by investigating which aspects of working memory (storage or processing) best predict GLAs in mice. We found that a component of working memory, selective attention, correlated with GLA comparably to working memory capacity. However, this relationship was not found for two other components of working memory, short-term memory capacity and duration. These results provide further evidence that variations in aspects of working memory and executive functions covary with general cognitive abilities.
Accumulating evidence indicates that the storage and processing capabilities of the human working memory system co-vary with individuals' performance on a wide range of cognitive tasks. The ubiquitous nature of this relationship suggests that variations in these processes may underlie individual differences in intelligence. Here we briefly review relevant data which supports this view. Furthermore, we emphasize an emerging literature describing a trait in genetically heterogeneous mice that is quantitatively and qualitatively analogous to general intelligence (g) in humans. As in humans, this animal analog of g co-varies with individual differences in both storage and processing components of the working memory system. Absent some of the complications associated with work with human subjects (e.g., phonological processing), this work with laboratory animals has provided an opportunity to assess otherwise intractable hypotheses. For instance, it has been possible in animals to manipulate individual aspects of the working memory system (e.g., selective attention), and to observe causal relationships between these variables and the expression of general cognitive abilities. This work with laboratory animals has coincided with human imaging studies (briefly reviewed here) which suggest that common brain structures (e.g., prefrontal cortex) mediate the efficacy of selective attention and the performance of individuals on intelligence test batteries. In total, this evidence suggests an evolutionary conservation of the processes that co-vary with and/or regulate "intelligence" and provides a framework for promoting these abilities in both young and old animals.
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