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Understanding and manipulating the dysregulation of interneurons in schizophrenia

Periodic Reporting for period 1 - SchizoFree (Understanding and manipulating the dysregulation of interneurons in schizophrenia)

Reporting period: 2021-05-01 to 2023-04-30

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.
1. To achieve local deletion of ErbB4 from the cortex and/or striatum we applied two different approaches: a genetic and a viral deletion model.

Our preliminary results suggest that genetic deletion of ErbB4 from cortex or striatum during early postnatal development is sufficient to cause hyperlocomotion in adulthood. Since we cannot completely rule out the involvement of other brain areas, we also employed a viral deletion strategy.
Removing ErbB4 by injecting a viral construct shortly after birth in the cortex resulted in tendencies towards hyperlocomotion in adulthood. Posthoc determination of the fraction of interneurons still expressing ErbB4 revealed that this approach led to approximately 60% removal of ErbB4 in the frontal cortex. Using the same method for the striatum, we did not see any difference between ErbB4 mutant or control mice injected with the virus. However, posthoc analysis of the brains showed that there was good removal of ErbB4 around the core of the injection site but not beyond that, thereby not affecting the entire striatum.
These experiments, however, are still ongoing and additional mice need to be added to the groups.


2. Explore the molecular mechanisms driving striatal hyperdopaminergia

We employ several approaches to unravel the mechanisms of striatal hyperdopaminergia in Lhx6-ErbB4 mutants involving both molecular and physiological experiments.

To this end, our results suggest that ErbB4 deletion of the entire forebrain interferes with the dopamine signalling pathways in the striatum, which could contribute to elevated levels of dopamine. In addition, preliminary physiological experiments indicate aberrant signalling and activity of striatal neurons during the onset and offset of movement.
To this end, our results indicate that ErbB4 signalling in the cortex or striatum alone are sufficient to drive hyperlocomotion and highlights the importance of proper PV functioning among both circuits. Our results further indicate that striatal hyperlocomotion is caused by alterations in dopamine signalling as well as the activity of striatal neurons. These results are important because they indicate that the altered PV circuitry caused by deletion of ErbB4 has profound impacts on dopamine transmission and that this effect is dependent on disruptions early during development.

Ongoing experiments are now exploring whether the hyperlocomotion in ErbB4 mutant mice is caused by increased activity of midbrain dopaminergic neurons resulting in enhanced presynaptic dopamine release and/or enhanced postsynaptic activity of dopamine receptors.

The final step of this project aims at normalizing interneuron function and whether this can intervene or prevent the progression of schizophrenia. This is important because it would implicate that manipulating interneuron networks in schizophrenia might be able to alleviate not only the positive but also the negative and cognitive symptoms. This would be a milestone in schizophrenia research offering a better recovery from the disease and therefore, improved quality of life for patients.
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