It takes a lot of genes to wire the human brain. Billions of cells, of a myriad different types have to be specified, directed to migrate to the right position, organised in clusters or layers, and finally connected to their appropriate targets. When the genes that specify these neurodevelopmental processes are mutated, the result can be severe impairment in function, which can manifest as neurological or psychiatric disease.

How those kinds of neurodevelopmental defects actually lead to the emergence of particular pathological states – like psychosis or seizures or social withdrawal – is a mystery, however. Many researchers are trying to tackle this problem using mouse models – animals carrying mutations known to cause autism or schizophrenia in humans, for example. A recent study from my own lab (open access in PLoS One) adds to this effort by examining the consequences of mutation of an important neurodevelopmental gene and providing evidence that the mice end up in a state resembling psychosis. In this case, we start with a discovery in mice as an entry point to the underlying neurodevelopmental processes.

In just the past few years, over a hundred different mutations have been discovered that are believed to cause disorders like autism or schizophrenia. In many cases, particular mutations can actually predispose to many different disorders, having been linked in different patients to ADHD, epilepsy, mental retardation or intellectual disability, Tourette’s syndrome, depression, bipolar disorder and others. These clinical categories may thus represent more or less distinct endpoints that can arise from common neurodevelopmental origins.

For a condition like schizophrenia, the genetic overlap with other conditions does not invalidate the clinical category. There is still something distinctive about the symptoms of this disorder that needs to be explained. I have argued that schizophrenia can clearly be caused by single mutations in any of a very large number of different genes, many with roles in neurodevelopment. If that model is correct, then the big question is: how do these presumably diverse neurodevelopmental insults ultimately converge on that specific phenotype? It is, after all, a highly unusual condition. The positive symptoms of psychosis – hallucinations and delusions, for example – especially require an explanation. If we view the brain from an engineering perspective, then we can say that the system is not just not working well – it is failing in a particular and peculiar manner.

To try to address how this kind of state can arise we have been investigating a particular mouse – one with a mutation in a gene called Semaphorin-6A. This gene encodes a protein that spans the membranes of nerve cells, acting in some contexts as a signal to other cells and in other contexts as a receptor of information. It has been implicated in controlling cell migration, the guidance of growing axons, the specification of synaptic connectivity and other processes. It is deployed in many parts of the developing brain and required for proper development in the cerebral cortex, hippocampus, thalamus, cerebellum, retina, spinal cord, and probably other areas we don’t yet know about.

Despite widespread cellular disorganisation and miswiring in their brains, Sema6A mutant mice seem overtly pretty normal. They are quite healthy and fertile and a casual inspection would not pick them out as different from their littermates. However, more detailed investigation revealed electrophysiological and behavioural differences that piqued our interest.

Because these animals have a subtly malformed hippocampus, which looks superficially like the kind of neuropathology observed in many cases of temporal lobe epilepsy, we wanted to test if they had seizures. To do this we attached electrodes to their scalp and recorded their electroencephalogram (or EEG). This technique measures patterned electrical activity in the underlying parts of the brain and showed quite clearly that these animals do not have seizures. But it did show something else – a generally elevated amount of activity in these animals all the time.

What was particularly interesting about this is that the pattern of change (a specific increase in alpha frequency oscillations) was very similar to that reported in animals that are sensitised to amphetamine – a well-used model of psychosis in rodents. High doses of amphetamine can acutely induce psychosis in humans and a suite of behavioural responses in rodents. In addition, a regimen of repeated low doses of amphetamine over an extended time period can induce sensitisation to the effects of this drug in rodents, characterised by behavioural differences, like hyperlocomotion, as well as the EEG differences mentioned above. Amphetamine is believed to cause these effects by inducing increases in dopaminergic signaling, either chronically, or to acute stimuli.

This was of particular interest to us, as that kind of hyperdopaminergic state is thought to be a final common pathway underlying psychosis in humans. Alterations in dopamine signaling are observed in schizophrenia patients (using PET imaging) and also in all relevant animal models so far studied.