2015/09/24 by Tuomo Mäki‐Marttunen, Geir Halnes, Mäki-Marttunen, Tuomo +17
Biochemistry, Genetics and Molecular Biology · #Gene expression and cancer classification #Receptor Mechanisms and Signaling #RNA and protein synthesis mechanisms
paper · pdf · doi:10.48550/arxiv.1509.07258
Background: Recent genome-wide association studies (GWAS) have identified a\nlarge number of genetic risk factors for schizophrenia (SCZ) featuring ion\nchannels and calcium transporters. For some of these risk factors, independent\nprior investigations have examined the effects of genetic alterations on the\ncellular electrical excitability and calcium homeostasis. In the present\nproof-of-concept study, we harnessed these experimental results for modeling of\ncomputational properties on layer V cortical pyramidal cell and identify\npossible common alterations in behavior across SCZ-related genes.\n Methods: We applied a biophysically detailed multi-compartmental model to\nstudy the excitability of a layer V pyramidal cell. We reviewed the literature\non functional genomics for variants of genes associated with SCZ, and used\nchanges in neuron model parameters to represent the effects of these variants.\n Results: We present and apply a framework for examining the effects of subtle\nsingle nucleotide polymorphisms in ion channel and Ca2+ transporter-encoding\ngenes on neuron excitability. Our analysis indicates that most of the\nconsidered SCZ- related genetic variants affect the spiking behavior and\nintracellular calcium dynamics resulting from summation of inputs across the\ndendritic tree.\n Conclusions: Our results suggest that alteration in the ability of a single\nneuron to integrate the inputs and scale its excitability may constitute a\nfundamental mechanistic contributor to mental disease, alongside with the\npreviously proposed deficits in synaptic communication and network behavior.\n