The molecular and cellular biology of enhanced cognition

Article (PDF Available)inNature Reviews Neuroscience 10(2):126-40 · March 2009with40 Reads
DOI: 10.1038/nrn2572 · Source: PubMed
Most molecular and cellular studies of cognitive function have focused on either normal or pathological states, but recent research with transgenic mice has started to address the mechanisms of enhanced cognition. These results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information. Here, we review these surprising findings and explore their implications to both mechanisms of learning and memory and to ongoing efforts to develop treatments for cognitive disorders. These findings represent the beginning of a fundamental new approach in the study of enhanced cognition.
    • "LTP at SC–CA1 synapse plays an important role in spatial learning and memory [26, 27]. Mutant mice with impaired LTP often show deficits in hippocampusdependent learning and memory [26, 27]. However, CD38 −/− mice showed comparable level of early-phase LTP (E-LTP) induced by a single pulse of high frequency (100 Hz) stimulation to WT controls (average of fEPSP slopes for last 5 min; CD38 +/+ , n = 6, 129.4 ± 7.3 %; CD38 −/− , n = 6, 130.1 ± 14.7 %; unpaired t-test; p = 0.9689;Fig. "
    [Show abstract] [Hide abstract] ABSTRACT: CD38 is an enzyme that catalyzes the formation of cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate, both of which are involved in the mobilization of Ca²⁺ from intracellular stores. Recently, CD38 has been shown to regulate oxytocin release from hypothalamic neurons. Importantly, CD38 mutations are associated with autism spectrum disorders (ASD) and CD38 knockout (CD38−/−) mice display ASD-like behavioral phenotypes including deficient parental behavior and poor social recognition memory. Although ASD and learning deficits commonly co-occur, the role of CD38 in learning and memory has not been investigated. We report that CD38−/− mice show deficits in various learning and memory tasks such as the Morris water maze, contextual fear conditioning, and the object recognition test. However, either long-term potentiation or long-term depression is not impaired in the hippocampus of CD38−/− mice. Our results provide convincing evidence that CD38−/− mice show deficits in various learning and memory tasks including spatial and non-spatial memory tasks. Our data demonstrate that CD38 is critical for regulating hippocampus-dependent learning and memory without modulating synaptic plasticity. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0195-5) contains supplementary material, which is available to authorized users.
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    • "Normally, NMDAR opening is associated with influx of Ca 2+ (in addition to Na + ). Small elevation of cytosolic [Ca 2+ ] serves as a signal for several processes such as learning and memory (Lee and Silva, 2009). However, under HP conditions, a large increase in NMDAR conductance will allow excessive neuronal Ca 2+ influx that may be associated with ''glutamate toxicity'' or even apoptosis (Orrenius et al., 2003). "
    [Show abstract] [Hide abstract] ABSTRACT: Professional deep-water divers, exposed to hyperbaric pressure (HP) above 1.1 MPa, develop High Pressure Neurological Syndrome (HPNS), which is associated with CNS hyperexcitability. It was previously reported that HP augments N-methyl-D-aspartate receptor (NMDAR) synaptic response, increases neuronal excitability and potentially causes irreversible neuronal damage. Our laboratory has reported differential current responses under HP conditions in NMDAR subtypes that contain either GluN1-1a or GluN1-1b splice variants co-expressed in Xenopus laevis oocytes with all four GluN2 subunits. Recently, we reported that the increase in ionic currents measured under HP conditions is also dependent on which of the eight splice variants of GluN1 is co-expressed with the GluN2 subunit. We now report that the NMDAR subtype that contains GluN1-4a/b splice variants exhibited 'dichotomic' (either increased or decreased) responses at HP. The distribution of the results is not Normal thus ANOVA test and clustering analysis were employed for statistical verification of the grouping. Furthermore, the calculated constants of alpha function distribution analysis for the two groups were similar, suggesting that the mechanism underlying the switch between an increase or a decrease of the current at HP is a single process, the nature of which is still unknown. This dichotomic response of the GluN1-4a/b splice variant may be used as a model for studying reduced response in NMDAR at HP. Successful reversal of other NMDAR subtypes response (i.e. current reduction) may allow the elimination of the reversible malfunctioning short term effects (HPNS), or even deleterious long term effects induced by increased NMDAR function during HP exposure.
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    • "Since the defi nition of the g-factor for " general cognitive ability " over a century ago (Spearman, 1904) and the characterization of the landmark patient H.M. in 1957 (Scoville and Milner, 1957), the fi eld of cognitive neuropsychology has been attempting to elucidate the brain structures and molecular players involved in these processes. However, most of this progress has been reached stepwise, working forward from brain structure to structure and molecule to molecule in a hypothesis-driven fashion (Lee and Silva, 2009). Recently, the advent of high-throughput genomic polymorphism scanning technologies has revolutionized our ability to search for the common genetic drivers of memory and other cognitive domains in a hypothesis-free manner (Goldberg and Weinberger, 2004; Fisher, 2006; Payton, 2006 Payton, , 2009 Potkin et al., 2009). "
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