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Dosage matters: Kainate Receptor Protein Levels and Mental Disease

北京大学神经科学研究所学术报告

 

 

Dosage matters:  Kainate Receptor Protein Levels and Mental Disease

 

报告人:Juan Lerma. Instituto de Neurociencias CSIC-UMH. San Juan de Alicante, Spain.

时间:2018年6月8日(周五)10:30

地点:北京大学医学部会议中心206

主持人:王韵教授

 

Throughout the central nervous system, excitatory and inhibitory synaptic transmission is tightly regulated to sustain proper brain function. The correct activity of circuits not only depends on their appropriate wiring, but also on the concerted interactions between presynaptically released transmitters and their postsynaptic receptors. Notably, establishing the adequate receptor number and type at synapses is fundamentally important to fine tune neuronal communication and brain plasticity associated to learning and memory. Normally, we tend to think about mutations that alter protein function as a source of disruption of this process that may lead to disease. However, the vulnerability of neurons to modest changes (increases or decreases) in levels of normal proteins is an emergent theme in brain disorders and may provide a new way to understand pathogenesis.  Indeed, pervasive brain pathologies can emerge because of variations in the dosage of certain genes and insertions, deletions, inversions and duplications may result in loss or gain of protein function. This seems to be the case of kainate receptors (KARs) and we have addressed this problem in two situations. First, a de novo duplication of the chromosome 11q23.3–q24.1 locus in which the gene GRIK4 (coding for a high affinity KAR subunit) lies has been identified in cases of autism, and more recently, a genome-wide linkage analysis found this gene to be associated to different endophenotypes in schizophrenia. We have evaluated a mouse overexpressing Grik4 in principal cells of the forebrain. These animals display signs of depression, anxiety and social impairment, closely reflecting the human endophenotypes associated to autism and schizophrenia. We found that modest increases in GluK4 protein are associated with increased synaptic gain at selected synapses in the amygdala complex and the hippocampus, resulting in unbalanced circuit outputs, which account for the behavioural abnormalities linked to these human diseases. Second, using a genetic strategy for dose normalization, we have examined the contribution of Grik1 over-dosage to Down syndrome (DS), where the chromosome 21, encompassing this gene, is triplicated in humans. We found in a transgenic mouse model of DS that inhibitory activity is affected in the hippocampus due to the excess of GluK1 protein and that this activity is redistributed along the somatodendritic axis of pyramidal cells. In summary, the synaptic effects of KAR genes overexpression recapitulate functional circuit activity in humans and may be significant to understand the ethiopathology of human disorders.