Dissecting the functional role of genetic and environmental risk factors associated with schizophrenia: towards patient-specific treatment paradigms
Schizophrenia is a complex severe neuropsychiatric disorder plausibly attributable to a combination of genetic abnormalities and environmental insults. It is clinically highly heterogeneous with patients presenting with varying symptom combinations and degrees of severity. While a strong genetic component is evident in schizophrenia, how gene variation contributes to the pathophysiology of the disorder is unknown. We hypothesize that schizophrenia, rather than being one disorder, is a spectrum of disorders with distinct genetic and environmental patterns and symptom presentations. Our goal is to dissect the functional role of genetic and environmental risk factors that are strongly associated with schizophrenia. This work could lead towards patient-specific treatment paradigms based on their genetic and environmental risk profile.
In order to test this hypothesis we will work alongside clinician, Prof. Suresh Sundram, head of adult Psychiatry at Monash Medical Centre. Prof. Sundram has so far analysed over 140 genes in 68 patient samples from post-mortem cortical brain tissue with the analysis of this expression study currently underway. Utilizing this valuable data we wish to align these studies with our genetic and environmental risk-associated animal model studies.
One such environmental risk factor that is highly associated with schizophrenia is prenatal exposure to infection. Indeed, epidemiological data suggests that infection (bacterial or viral), particularly during the second trimester of gestation, significantly increases the risk of developing schizophrenia in the offspring. This significant risk factor has been modelled in rodents by exposing pregnant mice to a viral-like injection. We have successfully utilized this model in our laboratory and have found both behavioural and electrophysiological neurological impairments relevant to schizophrenia.
Our first aim is to examine the same genetic targets as those assessed in the human brain cohort by Prof. Sundram in our maternal immune activation model to: 1. Determine the genetic signature of maternal immune activation as a risk factor for schizophrenia. 2. Compare this with human patients with schizophrenia to determine whether this pattern of gene expression is associated with a specific symptom group or patient cluster.3. To investigate which neural pathways are altered by this significant risk factor, with the potential to lead to novel therapeutic targets.
Cognitive impairments are: a core feature of schizophrenia; directly associated with functional outcome; and currently untreated by anti-psychotic medication. Novel drug targets are required to treat this debilitating symptom category. A second aim of this study is to utilize the human genetic data to identify specific genes that are highly associated with cognitive impairments. Using the highly innovative MICROMON genomics platform at Monash University we will develop genetically modified mice with alterations in specific genes identified in the human study. We will then test these mice using our novel highly translational touchscreen tasks to assess cognitive function in mice. These reward-based learning and memory tasks can test several aspects of cognition that align with human cognitive impairments found in schizophrenia. Using in vivo electrophysiological recordings we will test the functionality of specific neuronal populations during cognitive testing to determine how specific genetic deletions affect the firing of neurons during active learning and memory. The brains will then be analysed to determine which neural signalling pathways are altered by this genetic risk factor, with the potential to lead to novel therapeutic targets. Collectively our aim is to generate treatments that address patient-specific needs.
The behavioural neuroscience lab is working toward better treatments for psychiatric disorders. Psychiatric disorders are thought to be caused by a combination of genetic and environmental disturbances or ‘risk-factors’. The Behavioural Neuroscience laboratory models these risk factors in mice to understand at the molecular, physiological and behavioural level how these disturbances contribute to mental health. We use a number of different techniques, including genetic manipulation, mouse behavioural testing, molecular biology, in vivo electrophysiology and human clinical studies.
Dr Rachel Hill is a NHMRC Career Development Fellow and head of the Behavioural Neuroscience laboratory, Department of Psychiatry, Monash Medical Center. She currently holds competitive grants from the Australian government and US foundations, and supervises a team of post-doctorates, PhD students and honours students from Monash University.