Schizophrenia is a debilitating disease manifested by three clusters of symptoms: positive (psychosis, hallucinations, delusions), negative (lack of motivation, social withdrawal) and cognitive (deficits in memory and executive functions). Schizophrenia is usually diagnosed in late adolescence or early adulthood and the current therapies are based on the pharmacological treatment with antipsychotic drugs, which fail to alleviate the negative and cognitive symptoms, have many side effects and are ineffective in 30% of the patients. Importantly, the untreated negative and cognitive symptoms of the disease contribute the strongest to the long-term outcome of the patient and therefore, represent an unmet therapeutic need.
The pathophysiology of schizophrenia is still poorly understood but some core features have been replicated, such as elevated presynaptic dopamine function in the striatum and neuroanatomical and electrophysiological alterations in the medial prefrontal lobe, including the prefrontal cortex. Elevated striatal activity is thought to underlie the psychotic symptoms in schizophrenia; however, cognitive deficits are already present in patients before the onset of psychosis suggesting that maladapted changes in the striatum might be secondary to changes occurring in cortical networks. Previous work from the Marin and Rico labs has shown that reducing the excitatory synapses received by PV interneurons through the specific deletion of the tyrosine kinase receptor ErbB4 from these neurons display a schizophrenia-like phenotype through increased cortical excitability, impaired gamma oscillations and disrupted cognitive function. These findings stimulated a series of experiments showing that ErbB4 is required for the maturation of excitatory synapses onto PV interneurons in primates and that changes in ERBB4 splicing are associated with a reduction in excitatory synapses onto PV interneurons in schizophrenia patients. The aim of this fellowship was to disentangle the mechanisms and developmental trajectory underlying schizophrenia using the ErbB4 knockout mouse as a model and subsequently, to attempt to intervene with the progression of the disease by normalizing interneuron function.
This is important because it would identify biomarkers for earlier diagnoses of the disease and would provide a novel treatment strategy that can alleviate not only the positive but also the cognitive and negative symptoms.
The specific objectives of the project were:
1. Examine whether cortical and/or striatal ErbB4 deletion causes hyperdopaminergia
Understanding the origin underlying the maladaptive changes in schizophrenia is important because it allows defining a cause and consequence of the disease.
2. Explore the molecular mechanisms driving striatal hyperdopaminergia
Identifying the molecular mechanisms and developmental trajectory resulting in elevated striatal dopamine levels is necessary to define biomarkers and a time window for treatment intervention.
3. Test a novel treatment approach to treat and/or prevent the progression of schizophrenia
This is important because normalizing interneuron function might alleviate the negative and cognitive symptoms, which contribute the strongest to the long-term outcome of the disease and would significantly improve the quality of life of schizophrenia patients.
