Synaptic scaffold evolution generated components of vertebrate cognitive complexity

Nithianantharajah, Jess; Komiyama, Noboru H.; McKechanie, Andrew; Johnstone, Mandy; Blackwood, Douglas; Clair, David St; Emes, Richard D.; Lagemaat, Louie N. van de; Saksida, Lisa M.; Bussey, Timothy J.; Grant, Seth G. N.

doi:10.1038/nn.3276

Cited by 239 publications

(340 citation statements)

References 54 publications

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“…Hypotheses favor the implication of the scaffolding proteins of the postsynaptic region in higher cognitive processes. 40 The leucine-rich repeat (LRR) superfamily of proteins is an example of accelerated evolution involving genomic duplication, with 139 LRR proteins in humans compared with 66 in flies. This observation suggests that these proteins have a critical role in human-specific, higher order cognitive processes.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

et al. 2015

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Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.

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Section: Discussionmentioning

confidence: 99%

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

et al. 2015

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“…Since molecular pathways underlying cognitive processes might be evolutionarily conserved 16,17,18 and indeed the rodent hippocampus has long been the primary model for studying molecular processes related to learning and memory 19 , we next aimed to identify which of the human hippocampus co-expression modules are preserved in the healthy mouse hippocampus. To this aim, we carried out high-throughput sequencing of mRNA (RNA-seq) on snap-frozen hippocampus samples from 100 healthy adult mice and assessed the co-expression patterns between the mouse orthologs of human hippocampus module genes (Methods).…”

Section: Table 2)mentioning

confidence: 99%

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

et al. 2015

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2Genetic determinants of cognition are poorly characterized and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here, we used a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities including memory. Using exome sequence data from 6,871 trios, we find that M3 genes are also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease genes in the developed human brain, and provide empirical support for a convergent generegulatory network influencing cognition and neurodevelopmental disease.Cognition refers to human mental abilities such as memory, attention, processing speed, reasoning and executive function. Performance on cognitive tasks varies between individuals and is highly heritable 1 and polygenic 2,3 . However, to date, progress in identifying molecular genetic contributions to healthy human cognitive abilities has been limited 4,5 .A distinction can be made between cognitive domains such as the ability to apply acquired knowledge and learned skills (so called crystallized abilities) and fluid cognitive abilities such as the capacity to establish new memories, reason in novel situations or perform cognitive tasks accurately and quickly 6 . Notably, within individuals, performance on different measures of cognitive ability tend to be positively correlated such that people who do well in one domain, such as memory, tend to do well in other domains 7 . Seemingly disparate domains of cognitive ability also show high levels of genetic correlation in twin studies, typically in excess of 0.6 8 , and analyses using genome-wide similarity between unrelated individuals 3 (genome-wide complex trait analysis, GCTA) has also demonstrated substantial genetic correlation between diverse cognitive and learning abilities 9,10 . These studies suggest genes that influence human cognition may exert pleiotropic effects across diverse cognitive domains, such that genes regulating one cognitive ability might influence other cognitive abilities.Since impairment of cognitive function is a core clinical feature of many neurodevelopmental diseases including schizophrenia 11 , autism 12 , epilepsy 13 and intellectual disability (by definition), we sought to investigate gene-regulatory networks for human cognition and to determine their relationship to neurodevelopmental disease. An overview of our experimental design is provided in Supplementary Fig. 1. RESULTS Gene co-expression network a...

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“…Those proposals were speculative but studies of synaptic evolution are already providing encouraging findings. For example, Nithianantharajah et al (2013) studied the effects of mutations in genes coding for post-synaptic proteins that regulate NMDAR function on the behavior of mice. They adapted the CANTAB tests of conditioning, complex learning, attention, and cognitive control for use with mice.…”

Section: Are There Major Transitions In the Evolution Of Inferentialmentioning

confidence: 99%

On the functions, mechanisms, and malfunctions of intracortical contextual modulation

Phillips

Clark

Silverstein

2015

Neuroscience & Biobehavioral Reviews

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A broad neuron-centric conception of contextual modulation is reviewed and re-assessed in the light of recent neurobiological studies of amplification, suppression, and synchronization. Behavioural and computational studies of perceptual and higher cognitive functions that depend on these processes are outlined, and evidence that those functions and their neuronal mechanisms are impaired in schizophrenia is summarized. Finally, we compare and assess the long-term biological functions of contextual modulation at the level of computational theory as formalized by the theories of coherent infomax and free energy reduction. We conclude that those theories, together with the many empirical findings reviewed, show how contextual modulation at the neuronal level enables the cortex to flexibly adapt the use of its knowledge to current circumstances by amplifying and grouping relevant activities and by suppressing irrelevant activities.

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Synaptic scaffold evolution generated components of vertebrate cognitive complexity

Cited by 239 publications

References 54 publications

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

On the functions, mechanisms, and malfunctions of intracortical contextual modulation

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