Neuronal Excitability & Schizophrenia
In comparison to autism, schizophrenia has had a longer history of study. Yet in recent times, research into the condition seems to have received less money than autism itself, most likely due to the strong parental lobbying in favor of the latter. As such, the genetics data on autism abounds while that on schizophrenia is comparatively more sparse.
In 2014, Ripke et al. published an article that identified 108 genetic loci associated with schizophrenia, a big leap ahead in schizophrenia genomics. In a recent paper by Maki-Marttunen et al. (2016), the team published findings based on Ripke’s genetics data, using computer modeling of single-neuron physiology to determine whether common variants previously reported have the potential to alter neuron excitability and whether combinations of these common variants may worsen that effect.
While I won’t pretend to completely understand the methodology used in the paper (sadly, computer modeling and electrophysiology aren’t exactly my areas of expertise), the basic results of the research according to the authors suggest that at least the common variants associated with schizophrenia that lie within ion channel and calcium transporter encoding genes could indeed alter neuronal excitability and that this excitation may play a role in the pathophysiology of the condition. What’s more, they also show evidence to support the idea that a combination of individual genetic risk factors can exacerbate this effect, depending on the combination used.
The team used a basic computer model of a Layer 5 excitatory cortical neuron. These neurons tend to be the largest in size within the cortex, they integrate large amounts of information, and finally distribute that information to other cortical and subcortical structures, e.g., the thalamus.
Example of a layer 5 neocortical pyramidal cell.
Across the models studied, Maki-Marttunen et al. found that there were significant changes to the intracellular calcium response in reaction to both short stimuli and steady-state firing. They also noted that affected neurons often reacted differently following combinations of stimuli. For instance, in a normal neuron, if a stimulus is applied to the neuron body (soma) and then subsequently applied to the apical dendrite (mimicking the normal electric flow of information), this produces a larger calcium spike. In some affected neurons, such as those modeled with CACNA1I and SCN1A genetic variants, they showed changes to this spiking activity, sometimes reversing the order sensitivity (soma >>> apical dendrite) altogether (apical dendrite >>> soma).
The researchers also found that pre-pulse inhibition, in which the occurrence of an initial weaker stimulus can effectively block a second stronger stimulus from triggering neuron firing, was affected in some of the schizophrenic models, especially those involving calcium channels.
Finally, as mentioned, the team studied the effects on neuronal excitability of multiple common genetic variants together. This mimics the human model of complex diseases in which multiple small-effect common gene variants can have an additive effect with one another. The image below gives a good impression, for instance, how the addition of a CACNB2 variant added to a CACNA1C variant alters the stimulus response (overlapping wavy lines), and finally the addition of a third variant, CACNA1AI, which leads to the greatest deviation in stimulus-response. In short, the less these lines overlap one another, the bigger the effect.
So, this study not only suggests that at least in a subset of schizophrenia, disturbances to neuronal excitation potentially play important roles in the complex condition’s etiology. It also suggests that a polygenic model for schizophrenia may explain more cases than those rare gene mutations that have high penetrance but account for a very small percentage of the subpopulation (previous work has suggested something similar). This is known more broadly as the “Common Disease-Common Variant” hypothesis. Presumably, a similar argument could be made for a complex condition such as autism.