RESUMO
Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.
Assuntos
Anexina A2/fisiologia , Aprendizagem da Esquiva/fisiologia , Emoções/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Receptor 5-HT1B de Serotonina/fisiologia , Proteínas S100/fisiologia , Animais , Anexina A2/deficiência , Anexina A2/genética , Aprendizagem da Esquiva/efeitos dos fármacos , Depressão/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Genes Reporter , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ressonância Magnética Nuclear Biomolecular , Fosforilação/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/farmacologia , Tempo de Reação , Receptores de AMPA/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas S100/deficiência , Proteínas S100/genética , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Transdução GenéticaRESUMO
Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.
Assuntos
Complexo Relacionado com a AIDS/metabolismo , Depressão/complicações , Emoções/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Transtornos da Memória/etiologia , Receptores de Serotonina/metabolismo , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Benzopiranos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Depressão/genética , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Imunoprecipitação , Sistema de Sinalização das MAP Quinases/genética , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Mutantes , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Natação/psicologiaRESUMO
Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-D-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.3-5 microg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 microg dose of D-AP5, while doses of 0.3 and 1 microg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal D-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 microg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.
