Since changes in synaptic morphology are observed in learning and long- term potentiation, proteins known to contribute to the stability of synaptic contacts are of particular interest to understand memory functions. The overall goal is to investigate mRNA expression of agrin and integrins, and the factors that may mediate their expression in the rat hippocampus during long-term potentiation and spatial learning. Agrins and integrins are extracellular matrix proteins that may play an important role in synaptogenesis and the modification of existing synapses. Both morphological changes and/or synaptogenesis have been observed in learning and long-term potentiation. Preliminary studies find that again mRNA expression is induced in the brain of animals during learning a spatial navigational task. We have evidence also that agrin mRNA is expressed with hippocampal long-term potentiation. The hippocampus displays t least two forms of synaptic plasticity, one that requires the activation of the glutaminergic receptor displays at least two forms of synaptic plasticity, one that requires the activation of the glutaminergic receptor N-Methyl-D-Aspartate (NMDA) and another that requires the activation of opiodergic receptors. Opioids are found in the lateral perforant path to area CA3, the lateral perforant path to dentate gyrus, and the mossy fiber to area CA3. Thus gene expression may be modulated by the activation of NMDA and opioid receptors. Agrin and integrin mRNA expression during long-term potential will be investigated in the perforant path-dentate gyrus and the perforant path-CA3 pathways using awake freely-moving rats. These pathways expressed NMDA and opioid- receptor dependent long-term potentiation.
Specific Aim 1 will investigate temporal mRNA expression of agrin and integrins during long-term potentiation. Naloxone and selective opioid or NMDA receptor antagonists will be used to investigate if the activation of opioid or NMDA receptors is involved in agrin or integrins mRNA expression.
Specific Aim 2 will investigate the time course induction of agrin during spatial learning of the Morris water maze task. Naloxone and selective opioid receptor and NMDA receptor antagonists will be used to investigate if the activation of opioid or NMDA receptors is involved in agrin or integrins mRNA expression during this form of learning. These studies will investigate also if the impairment in learning observed with the administration of opioid or NMDA receptor antagonists parallel the blockade of agrin and integrin mRNA expression.
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