RESUMEN
Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/-. However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.
Asunto(s)
Bombesina , Espinas Dendríticas , Hipocampo , Plasticidad Neuronal , Receptores de Bombesina , Estrés Psicológico , Animales , Ratones , Bombesina/genética , Bombesina/metabolismo , Enfermedad Crónica , Espinas Dendríticas/genética , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Depresión/genética , Depresión/metabolismo , Depresión/patología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Receptores de Bombesina/genética , Receptores de Bombesina/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
Both bombesin receptor-activated protein (BRAP) and its mouse homolog have been found to be expressed in bronchial epithelia but with unclear functions. Using electron microscopy combined with histological assays, we found that BRAP homolog deficiency in mice led to abnormal tracheal cilia. Rab-3A-interacting protein (Rabin8), a protein that might play a role in cilia development, was screened by yeast two-hybrid and further verified to have interaction with human BRAP by co-immunoprecipitation and pulldown assays. The expression levels of Rabin8, together with acetylated α-tubulin, a marker of cilia, were either downregulated by knockdown of BRAP or upregulated by overexpression of BRAP in cultured immortalized human bronchial epithelial cells. These results reveal a role for BRAP in airway cilia formation.