Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

Abstract

Background Recent genome-wide association studies 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 cells and identified possible common alterations in behavior across SCZ-related genes. Methods We applied a biophysically detailed multicompartmental 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 calcium 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 the previously proposed deficits in synaptic communication and network behavior.

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

“…Finally, the theta neuron model is a simple and abstract neuron model and does not capture electrophysiological differences between BCs and ChCs found experimentally [30]. Interestingly, genetic variants of risk genes for schizophrenia include a variety of genes coding for ion channels or ion transporters, which have been shown to alter cell excitability [24,26] and network oscillations [25]. Such variants might potentially amplify electrophysiological differences between BCs and ChCs and thereby change their relative roles in the generation of gamma/beta oscillations.…”

Multifactorial Modeling of Impairment of Evoked Gamma Range Oscillations in Schizophrenia

“…In a recent modeling study, (Mäki-Marttunen et al, 2016) show that the interaction of small changes to parameters regulating ion channels and internal calcium concentrations in cortical pyramidal cells, can drastically change the excitability of the cells. The novelty of their approach is, that the parameter changes implemented in their model are directly derived from susceptibility genes identified from a large genome-wide association study (Ripke et al, 2014).…”

Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia

“…70,71 The basic idea is to use experimentally obtained mapping between SCZ risk variants and the cellular/network behavior to constrain computation models of single neurons and neuronal networks providing mechanistic biophysical basis for the SCZ functional endophenotype. A detailed ‘realistic’ model of cortical column 72,73 has recently become available because of a decade-long effort by the Blue Brain Project currently continuing under the umbrella of the Human Brain Project.…”