Background: Recent genome-wide association studies (GWAS) have identified a
large number of genetic risk factors for schizophrenia (SCZ) featuring ion
channels and calcium transporters. For some of these risk factors, independent
prior investigations have examined the effects of genetic alterations on the
cellular electrical excitability and calcium homeostasis. In the present
proof-of-concept study, we harnessed these experimental results for modeling of
computational properties on layer V cortical pyramidal cell and identify
possible common alterations in behavior across SCZ-related genes.
Methods: We applied a biophysically detailed multi-compartmental model to
study the excitability of a layer V pyramidal cell. We reviewed the literature
on functional genomics for variants of genes associated with SCZ, and used
changes in neuron model parameters to represent the effects of these variants.
Results: We present and apply a framework for examining the effects of subtle
single nucleotide polymorphisms in ion channel and Ca2+ transporter-encoding
genes on neuron excitability. Our analysis indicates that most of the
considered SCZ- related genetic variants affect the spiking behavior and
intracellular calcium dynamics resulting from summation of inputs across the
dendritic tree.
Conclusions: Our results suggest that alteration in the ability of a single
neuron to integrate the inputs and scale its excitability may constitute a
fundamental mechanistic contributor to mental disease, alongside with the
previously proposed deficits in synaptic communication and network behavior
