Final Report Summary - GABACORT (Analysis of Neuregulin-1 function in the maturation of cortical GABAergic interneurons: implications for the etiology of schizophrenia)
Although many studies have demonstrated that the risk to develop schizophrenia has a strong genetic component, the specific factors that give rise to the disorder are still not well understood. In the last years, several independent genetic studies have identified Neuregulin 1 (Nrg1) and its receptor ErbB4 as major risk genes for schizophrenia. Collectively, these data strongly suggest that impairment in Nrg1/ErbB4 signalling plays a key role in the molecular mechanism underlying the development of this mental disorder. Over the past few years we have studied the function of this signalling system in the development of Gabaergic synapses.
Pietro Fazzari a join post doc of Oscar Marin and my lab was granted (under my supervision) with a Marie-Curie postdoctoral fellowship (Gabacort - Project No. 220731). We found that ErbB4 is expressed by cortical Gabaergic interneurons, and specifically in Parvalbumin-expressing cells (Baskets and Chandelier neurons). At the subcellular level, ErbB4 is expressed in GABAergic terminals contacting the soma and axon initial segment (AIS) of pyramidal neurons, and postsynaptically in the postsynaptic densities (PSD) of Gabaergic dendrites receiving excitatory input. Our in vitro data suggested that Nrg1 promotes Gabaergic axonal arbor differentiation. Overexpression of Nrg1-CRD in pyramidal cells both in vitro and in vivo promoted Gabaergic synapse formation. Moreover, loss of function experiments using in vivo utero infection demonstrated that ErbB4 is required for normal synapse formation in Chandelier cells. These data is consistent with a decrease in the frequency of mIPSC in the interneuron-ErbB4 mutants, due to a decrease in the number of Gabaergic synapses. In addition, loss of ErbB4 caused a decrease in excitatory inputs impinging onto Parvalbumin interneurons.
In conclusion, our experiments demonstrate that loss of ErbB4 function in the mouse reduces the number of synapses made by chandelier cells, one of the most salient pathological features of individuals with schizophrenia. In addition, postsynaptic ErbB4 expression is also required for PV-expressing interneurons to receive a normal complement of excitatory synapses. The function of these neurons is intimately linked to the generation of gamma-frequency synchronisation, an emergent property of cortical circuits that is linked to information processing and working memory in normal individuals and whose disruption contributes to the cognitive deficits of schizophrenia.
Potential socio-economic impact.
Schizophrenia is a severe mental disease that usually produces a lifetime of disability and emotional distress, affecting 1 % of the population worldwide. Schizophrenia is the most chronic and disabling of the psychotic disorders and it is among the most costly for our society in terms of medical expenditure and loss of productivity. Indeed, some studies performed with European populations suggested that 79 % of the schizophrenic patients undertook no work of any kind, and 65 % were single, therefore showing a high level of family dependency (Schizophrenia Research, 69 (2-3): 125, 2004).
There is mounting evidence suggesting that Neuregulin-ErbB4 represent target molecules for developing new therapies for this devastating disorder, the schizophrenia. Using as a model the mouse, we have shown a plausible molecular mechanism by which Gabaergic circuits might be abnormal in patients suffering Schizophrenia. We have delivered a good model for futures studies in the Schizophrenia field for our group and others which in a mid- and long-term period will certainly allow to deliver potential new drugs for using in the therapy of this disease. In addition, we do not rule out the possibility that our future projects generate results that may led to a patent or the establishment of relations with industry. Therefore, from a social and economic perspective, our contribution will benefit undoubtedly the European Society in the future.
Pietro Fazzari a join post doc of Oscar Marin and my lab was granted (under my supervision) with a Marie-Curie postdoctoral fellowship (Gabacort - Project No. 220731). We found that ErbB4 is expressed by cortical Gabaergic interneurons, and specifically in Parvalbumin-expressing cells (Baskets and Chandelier neurons). At the subcellular level, ErbB4 is expressed in GABAergic terminals contacting the soma and axon initial segment (AIS) of pyramidal neurons, and postsynaptically in the postsynaptic densities (PSD) of Gabaergic dendrites receiving excitatory input. Our in vitro data suggested that Nrg1 promotes Gabaergic axonal arbor differentiation. Overexpression of Nrg1-CRD in pyramidal cells both in vitro and in vivo promoted Gabaergic synapse formation. Moreover, loss of function experiments using in vivo utero infection demonstrated that ErbB4 is required for normal synapse formation in Chandelier cells. These data is consistent with a decrease in the frequency of mIPSC in the interneuron-ErbB4 mutants, due to a decrease in the number of Gabaergic synapses. In addition, loss of ErbB4 caused a decrease in excitatory inputs impinging onto Parvalbumin interneurons.
In conclusion, our experiments demonstrate that loss of ErbB4 function in the mouse reduces the number of synapses made by chandelier cells, one of the most salient pathological features of individuals with schizophrenia. In addition, postsynaptic ErbB4 expression is also required for PV-expressing interneurons to receive a normal complement of excitatory synapses. The function of these neurons is intimately linked to the generation of gamma-frequency synchronisation, an emergent property of cortical circuits that is linked to information processing and working memory in normal individuals and whose disruption contributes to the cognitive deficits of schizophrenia.
Potential socio-economic impact.
Schizophrenia is a severe mental disease that usually produces a lifetime of disability and emotional distress, affecting 1 % of the population worldwide. Schizophrenia is the most chronic and disabling of the psychotic disorders and it is among the most costly for our society in terms of medical expenditure and loss of productivity. Indeed, some studies performed with European populations suggested that 79 % of the schizophrenic patients undertook no work of any kind, and 65 % were single, therefore showing a high level of family dependency (Schizophrenia Research, 69 (2-3): 125, 2004).
There is mounting evidence suggesting that Neuregulin-ErbB4 represent target molecules for developing new therapies for this devastating disorder, the schizophrenia. Using as a model the mouse, we have shown a plausible molecular mechanism by which Gabaergic circuits might be abnormal in patients suffering Schizophrenia. We have delivered a good model for futures studies in the Schizophrenia field for our group and others which in a mid- and long-term period will certainly allow to deliver potential new drugs for using in the therapy of this disease. In addition, we do not rule out the possibility that our future projects generate results that may led to a patent or the establishment of relations with industry. Therefore, from a social and economic perspective, our contribution will benefit undoubtedly the European Society in the future.