Abstract
Major neuropsychiatric diseases, including schizophrenia and bipolar disorder, deteriorate higher brain functions leading to disorganized thinking and cognitive decline. Available treatments can reduce the symptoms of both diseases however they are not effective in reversing cognitive dysfunction. Targeting cognition, we have generated mouse models in order to understand mechanisms leading to major neuropsychiatric disorders and develop novel treatments for these diseases. We have shown that erythropoietin (EPO), a hematopoietic growth factor with multifaceted neuroprotective properties, has also beneficial effects on cognition under both healthy and pathological conditions. Treatment of young (28 days old), healthy mice with EPO for 3 weeks resulted in a significant improvement in hippocampus dependent contextual memory task. Electrophysiological and histological analysis on hippocampal slices obtained from EPO-treated mice showed that EPO modulates excitatory and inhibitory neurotransmission without affecting the total synapse number. In order to study effect of EPO under pathological conditions, we have developed an animal model of unilateral parietal injury. Application of a small experimental cryolesion to the right parietal cortex of juvenile mice led to cognitive impairment and bilateral brain atrophy, highly reminiscent of the pathophysiology observed in schizophrenia. Whereas the total number of neurons and astrocytes in these brain regions remained unaltered, pointing to a non-gliotic neurodegeneration (as seen in schizophrenia), lesion caused early onset and persistent microglial activation, decrease in oligodendrocytes/myelin associated proteins, relative increase in determinants of GABAergic neurotransmission and a reduction of a presynaptic protein, synapsin 1. Global brain atrophy and cognitive decline as well as changes in cellular composition/protein expression could be prevented by early EPO intervention. Although the detailed mechanisms remain to be defined, these profound EPO effects open new ways for prophylaxis and therapy of neuropsychiatric diseases, e.g. schizophrenia.
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