Among the various (and few) significant results of recent landmark whole-genome analyses (involving more than 54,000 participants) on schizophrenia (covered here and here), there was really just one consistent result – linkage to the 6p21-22 region containing the immunological MHC loci. While there has been some despair among professional gene hunters, one man’s exasperation can sometimes be a source of great interest and opportunity for others – who – for many years – have suspected that early immunological infection was a key risk factor in the development of the disorder.
Such is the case in the recent paper, “Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats” by Baharnoori et al., [doi: 10.1016/j.schres.2008.10.003]. In this paper, the authors point out that Emil Kraepelin, who first described the disorder we now call schizophrenia, had suggested that childhood inflammation of the head might be an important risk factor. Thus, the immunopathological hypothesis has been around since day 0 – a long time coming I suppose.
In their research article, Baharnoori and colleagues have taken this hypothesis and asked, in a straightforward way, what the consequences of an immunological challenge on the developing brain might look like. To evaluate this question, the team used a Sprague-Dawley rat model and injected pregnant females (intraperitoneally on embryonic day 16) with a substance known as lipopolysaccharide (LPS) which is known to mimic an infection and initiate an immune response (in a manner that would normally depend on the MHC loci found on 6p21-22). Once the injections were made, the team was then able to assess the consequences to various aspects of brain and behavior.
In this paper, the team focused their analysis on the development of the frontal cortex and the hippocampus – 2 regions that are known to function poorly in schizophrenia. They used a very, very focused probe of development – namely the overall shape, branching structure and spine formations on pyramidal cells in these regions – via a method known as Golgi-Cox staining. The team presents a series of fantastically detailed images of single pyramidal cells (taken from postnatal day 10, 35 and 60) from animals who’s mothers were immunologically challenged and those who were unexposed to LPS.
Briefly, the team finds that the prenatal exposure to LPS had the effect of reducing the number of dendritic spines (these are the aspects of a neuron that are used to make synaptic connections with other neurons) in the developing offspring. Other aspects of neuronal shape were also affected in the treated animals – basically amounting to a less branchy, less spiny – less connectable – neuron. If that’s not a basis for a cognitive disorder than what else is? Indeed, the authors point out that such spines are targets – in early development – for interneurons that are essential for long-range gamma oscillations that help distant brain regions function together in a coherent manner (something that notably does not happen in schizophrenia).
Thus, there is many a reason (54,000 strong) to want to better understand the neuro-immuno-genetic-developmental mechanisms that can alter neuronal structure. Exciting progress in the face of recent genetic setbacks!