Year

2014

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Schizophrenia is a serious psychiatric disorder causing a wide range of devastating impairments. A combination of several genetic and environmental factors is considered to result in a range of neurobiological changes underlying the symptom spectrum of schizophrenia. Differences in the γ-aminobutyric acid (GABA)ergic, glutamatergic and dopaminergic neurotransmitter systems have been most consistently observed in patients with schizophrenia. Current pharmacological treatment options for patients with schizophrenia are, however, still limited in their ability to address the range of symptoms and identified neurobiological differences.

Substantial evidence from human studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia, with further support from animal studies. Acute NRG1 signalling has been shown to affect GABAergic and glutamatergic neurotransmission in vitro in the prefrontal cortex (PFC) and hippocampus, two regions strongly linked to the symptomatology of schizophrenia. Due to the acute signalling properties of NRG1 in attenuating schizophrenia-relevant neurotransmission, a therapeutic potential of the NRG1 signalling system for the treatment of schizophrenia has been hypothesized, but never explored.

In the present PhD thesis I assessed the possible antipsychotic-like characteristics of NRG1 treatment on schizophrenia-relevant behavioural and molecular impairments focusing on GABAergic and glutamatergic signalling. I modelled schizophrenia-like impairments in adult male mice by acute phencyclidine (PCP). Acute PCP treatment in mice has been shown to induce a wide spectrum of schizophrenia-relevant symptoms, including hyperlocomotion, impaired sensorimotor gating and neurotransmission impairments. This treatment paradigm is therefore widely used as a first step in antipsychotic drug development studies.

In my first study, I examined the effects of concurrent NRG1 and PCP treatment on locomotor activity and sensorimotor gating. Central and peripheral NRG1 administration dose-dependently prevented PCP-induced hyperlocomotion and prepulse inhibition impairment. Advancing on these findings, I then studied the effects of NRG1 application on acute neurotransmission in the presence of PCP by microdialysis in the PFC and hippocampus of freely moving mice. In the PFC, NRG1 reduced glutamate and glycine levels, while combined NRG1 and PCP treatment triggered an increase in extracellular glycine. In the hippocampus, PCP treatment triggered a sig- nificant increase in GABA levels without affecting glutamate or glycine. The GABA increase was not observed following combined NRG1 and PCP treatment, suggesting that NRG1 prevented the PCP effect. An increase in glycine was again observed following combined treatment, here accompanied by a reduction in glutamate levels.

In my final study, I treated cells from primary frontal cortex cultures with NRG1 in the presence of PCP, measuring components of the GABAergic system relevant to the pathophysiology of schizophrenia. PCP changed the mRNA expression of GABA producing enzymes and the calcium binding protein parvalbumin. Combined treatment with NRG1 dose-dependently prevented these PCP-induced expression changes in the frontal cortex cells.

Prevention of PCP-induced hyperlocomotion and PPI impairments demonstrates a clear involvement of the NRG1 signalling pathway in neuronal circuits relevant for spontaneous behaviour. The region specific influence of NRG1 on glutamate and glycine levels confirms the involvement of NRG1-ERBB signalling in adult excitatory neurotransmission. Furthermore, preventing the PCP-induced GABA increase in the hippocampus provides support for a functional role in inhibitory neurotransmitter signalling. An involvement of NRG1 in the regulation of inhibitory neurotransmission was further supported by in vitro frontal cortex experiments where NRG1 treatment prevented changes to GABA producing enzymes.

The combined outcomes of my experiments provide initial support for potential antipsychotic- like characteristics of NRG1 treatment in a mouse model with induced schizophrenia-relevant behavioural and molecular impairments. The observed efficacy of peripherally administered NRG1 to prevent PCP-induced behavioural deficits indicates its potential as a new therapy for schizophrenia patients. Exploring the consequences of long-term NRG1 treatment on a broader spectrum of behavioural performance and molecular changes, particularly of the dopaminergic system, will be required to advance on the present findings and take the next step towards a potential suitability of NRG1 treatment in a clinical setting.

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