ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
GLUTAMATE AND PSA-NCAM DEPENDENT HIPPOCAMPAL SYNAPTIC REMODELLING: CORRELATION WITH AN EXPERIMENTAL MODEL OF DEPRESSION AND ITS PHARMACOLOGICAL TREATMENT
Autor/es:
PODESTÁ MF; CODAGNONE, M; LORENZO LÓPEZ, JR; LÓPEZ, M; BRUSCO, A; WIKINSKI, S; REINÉS, A
Lugar:
San Diego, USA
Reunión:
Congreso; 40th Annual Meeting Neuroscience 2010; 2010
Institución organizadora:
Society for Neuroscience (SFN)
Resumen:
Dendritic atrophy of hippocampal CA3 neurons and dysfunction of hippocampal plasticity have been proposed to play a critical role in the pathophysiology of depression and are both probably related to excessive glutamate (GLU) release. Based on our previous results showing decreased hippocampal synaptophysin (SYN) and PSD-95 expression in animals exposed to the learned helplessness (LH) paradigm, an experimental model of depression, we examined the synapse morphology and cell adhesion molecule expression in the LH paradigm, with and without fluoxetine (FLX) treatment. In primary hippocampal neurons we analyzed the impact of GLU hyperstimulation on synapse morphology and synaptic protein expression. Electron microscopy studies showed increased synaptic cleft width at the CA3 synapses of LH animals.  While postsynaptic density (PSD) length decreased, PSD width increased rendering similar values in total area. In LH group synaptic vesicles per synapse (SV/S) ratio presented extreme low or high values, whereas in control rats SV/S ratio was homogenous. These results are compatible with plastic and synaptic connectivity alterations. Interestingly LH rats also showed decreased CA3 immunostaining for NCAM and PSA-NCAM, cell adhesion molecules implicated in plasticity and expressed by GLU neurons. In vitro, GLU hyperstimulation of hippocampal neurons in culture presented reduced MAP-2, NCAM and PSA-NCAM immunostaining. Whereas PSD-95 and SYN puncta number diminished, individual puncta size was not modified for PSD-95 and was increased for SYN. Our results indicate that excessive neuronal exposure to GLU induces synaptic changes in vitro that resemble those observed in LH animals. Surprisingly FLX treatment of LH rats recovered synaptic cleft width values, increased total synaptic vesicle number particuly by augminting reserve synaptic vesicles. Also strongly reduced NCAM and increased PSA-NCAM levels in CA3 in LH animals. Results support the hypothesis that GLU hyperactivity in the CA3 of LH rats could reduce cell adhesion molecule expression and that FLX action could involve PSA-NCAM dependent synaptic remodelling that might lead to neuronal connectivity normalization. Grants PICT34397, UBACYT B422