Friday, October 12, 2012

It’s not the crime, it’s the cover-up: reactivity in the developing brain and the emergence of schizophrenia

In thinking about the causes of schizophrenia, a central question keeps coming up: why does the brain end up in that particular state? Despite a high degree of variability in presentation and difficulties in defining it precisely, there is a recognisable syndrome that we call schizophrenia. This has a number of characteristic attributes, most striking of which are psychotic symptoms such as hallucinations, delusions and disorganised thoughts. These are truly, deeply strange phenomena that require an explanation: why do brain systems fail in that particular way? More to the point, why does that particular brain state emerge in so many people from so many different initial causes?

Because though we don’t know all the causes of this disorder, we know for sure that there are a lot of them. On the genetic front, a large number of distinct, rare mutations in different genes (or regions of the genome) are associated with a high risk for schizophrenia. Genome-wide association studies have implicated additional loci that may modify risk weakly. There are also many environmental risk factors identified through epidemiological studies, such as maternal infection, cannabis use, migration, urban living, winter birth, obstetric complications and others, each of which modestly increases risk, statistically-speaking. Currently, we do not know how all these risk factors interact and there is ongoing debate about their relative importance. What we can say with certainty, however, is that the causes of this disorder are extremely heterogeneous.

The other thing that there is general agreement on is that schizophrenia is a neurodevelopmental disorder. Even though the overt symptoms of psychosis or cognitive decline do not emerge until adolescence or even later, the evidence is compelling that in most cases the initial insults probably occurred decades earlier during fetal or postnatal development. So, the question becomes: why do defects in neural development of so many different types all lead to this same, strange condition? Why is psychosis such an easy phenotype to get to?

This is where Richard Nixon comes in.

The Watergate scandal inspired the saying “it’s not the crime, it’s the cover-up that gets you”*. In regard to schizophrenia, the idea is that mutations in various genes (or environmental insults) may disrupt neural development in diverse ways, affecting different cellular processes and causing different primary phenotypes. The reason that all these different insults can lead to the same outcome lies in the way the developing brain reacts (or over-reacts) to them.

This idea is appealing because it is very parsimonious – it provides a common pathway to the end-state we recognise as schizophrenia, even from extremely diverse starting points. It can also explain the high incidence of the condition: mutations in many, many different genes can cause the disorder because it is an emergent property of the developing brain and not related directly to the genes’ primary functions. It also has a lot of experimental support, especially for the example of psychosis, where many investigations have highlighted a central role for the dopamine system.

Dopamine attracted attention because both typical and atypical antipsychotics target the dopamine D2 receptor and their efficacy is related to their affinity for this receptor. Conversely, amphetamine, which increases dopamine levels, can induce psychotic symptoms. More direct evidence of changes in the dopamine system comes from imaging studies of schizophrenia patients, which have found alterations in dopamine synthesis and release and in baseline occupancy of D2 receptors in the striatum. These findings are complicated and not uncontroversial, but the general convergence of different lines of evidence strongly supports the model that a disturbance in dopaminergic signaling is causing psychosis (or at least contributing to it).

This led many people to look for variation in genes encoding components of the dopaminergic system in patients with schizophrenia, without success. No variation in these genes was found to be associated with risk of the disease. This does not undermine the association of dopamine with the state of psychosis – it simply suggests that the primary changes are in other systems and that the alterations to the dopamine system are secondary reactions.

Animal models have shown how such changes can come about. Many different animal models have been generated to try and model aspects of schizophrenia. Some expose animals to known environmental risk factors, others use pharmacological or surgical procedures and, more recently, a growing number recapitulate high-risk mutations in mice.

With a couple exceptions, none of these manipulations targets the dopamine system directly. Nevertheless, in many of these models, an altered state of dopamine signaling emerges. This can be observed in a suite of behaviours (such as hyperlocomotion and altered pre-pulse inhibition), which are characteristic of animals in which the dopamine system is hyper-responsive. Many of these animal models show reversal of these phenotypes with antipsychotics and heightened sensitivity to drugs like amphetamine. Alterations in dopamine release, in levels of dopamine receptors or other parameters have also been directly observed in some models.

So, the evidence from animal models converges with that from humans – changes to the dopaminergic system can emerge as secondary consequences of a range of different primary insults. One model has been particularly informative as to how these changes can come about. If young postnatal rats are given a lesion to a particular brain region, the ventral hippocampus, then they will later – only after rat “adolescence” – develop symptoms that parallel psychosis in humans, as described above. These symptoms can be reversed by antipsychotics and are correlated with changes in dopaminergic signaling, but these arise in very different regions of the brain to the one with the lesion.

The circuitry driving these changes has been worked out in great detail by Anthony Grace, Patricio O’Donnell and their respective colleagues. The lesion to the ventral hippocampus renders the connected region, the ventral subiculum hyperactive. In turn, this region projects to part of the midbrain, where most dopaminergic neurons live. It leads to excessive dopamine neuron excitability, which alters the drive to the target areas of these neurons in the striatum and cortex. Crucially, the development of these areas in turn, is changed as they develop under a regime of altered activity.

The initial connectivity of the brain is specified by a molecular program of axon guidance and synaptic connectivity cues, but this generates only a rough map. This scaffold is extensively modified by activity. The developing brain is not silent – it is extremely active, electrically. It has its own rhythms and modes of activity, quite different from adults, and these intrinsically generated patterns of electrical firing are essential for driving the wiring of neuronal circuits. Any defect in initial wiring that results in altered architecture of local circuits is likely to also alter patterns of activity, which will propagate through developing circuits to connected areas, inducing a cascade of knock-on effects.

In some cases, neurons may attempt tocompensate for altered levels of activity, but these attempts actually exacerbate the situation, compounding the initial defect. This can happen in particular in cases where the initial molecular defect impairs not just the patterns of activity but the systems that monitor and interpret that activity. Neurons may be getting excessive activity but “think” they are getting less, causing what would normally be homeostatic responses to instead amplify the initial difference. 

So, changes in dopaminergic signaling in cortex and striatum – the signatures of psychosis – can emerge as very downstream effects of diverse initial disturbances in brain development. This is by no means the whole explanation of the state we call schizophrenia or even of the symptoms of psychosis, but it certainly seems to contribute to it. There are many other changes that also emerge over development in both human patients and animal models, notably including a suite of biochemical changes in particular inhibitory interneurons in the cortex. Again, the pathways through which these changes come about are beginning to be worked out.

In this model, the phenotype of schizophrenia is an emergent property of the developing brain – it is not linked in any direct way to the primary etiological factors. In the plot of a classic farce, a minor misunderstanding leads to catastrophe when the hapless protagonist overcompensates for it, getting himself into deeper and deeper trouble (think Basil Fawlty). Things get progressively out of hand and hilarity ensues. When the equivalent happens in brain development, insanity ensues.

*With thanks to David Dobbs for the meme, which came up in a really interesting conversation on how genotypes relate to psychological phenotypes (very indirectly).


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