kt-5720 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

It has been reported that training in behavioral tasks modifies the ability to induce long-term potentiation (LTP) in an N-methyl-D-aspartate receptor (NMDAR)-dependent manner. This receptor leads to calcium entry into neuronal cells, promoting the activation of protein kinases as protein kinase A (PKA) and protein kinase C (PKC), which contribute significantly to the formation of different types of memories and play a pivotal role in the expression of LTP. Our previous studies involving the insular cortex (IC) have demonstrated that induction of LTP in the basolateral amygdaloid nucleus (BLA)-IC projection prior to conditioned taste aversion (CTA) training enhances the retention of this task. Recently, we showed that CTA training triggers a persistent impairment in the ability to induce subsequent synaptic plasticity on the BLA-IC pathway in a protein synthesis-dependent manner, but the underlying molecular mechanisms remain unclear. In the present study we investigated whether the blockade of NMDAR, as well as the inhibition of PKC and PKA affects the CTA-dependent impairment of the IC-LTP. Thus, CTA-trained rats received high frequency stimulation in the Bla-IC projection in order to induce LTP 48 h after the aversion test. The NMDAR antagonist CPP and the specific inhibitors for PKC (chelerythrine) and PKA (KT-5720) were intracortically administered during the acquisition session. Our results show that the blockade of NMDAR and the inhibition of PKC activity prevent the CTA memory-formation as well as the IC-LTP impairment. Nevertheless, PKA inhibition prevents the memory formation of taste aversion but produces no interference with the CTA-dependent impairment of the IC-LTP. These findings reveal the differential roles of protein kinases on CTA-dependent modification of IC-LTP enhancing our understanding of the effects of memory-related changes on synaptic function.

Topics: Animals; Avoidance Learning; Benzophenanthridines; Carbazoles; Cerebral Cortex; Cyclic AMP-Dependent Protein Kinases; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Long-Term Potentiation; Male; Piperazines; Protein Kinase C; Pyrroles; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Taste

Presenilin (PS) plays an essential role in intramembranous gamma-secretase processing of amyloid precursor protein (APP) and several membrane-bound proteins. Here we report that selective accumulation of a membrane-tethered deleted in colorectal cancer (DCC) derivative (DCC-alpha) correlates with extensive neurite outgrowth in transfected neuroblastoma cells and axodendritic connectivity associated with increased spine density in cortical neurons derived from PS1(-/-) embryos, as well as wild-type neurons treated with gamma-secretase inhibitors. cAMP-dependent signaling was also increased in both the neuroblastoma and cortical neuron systems. As a physiological consequence of increases in axodendritic connectivity and in the magnitude of cAMP-dependent signaling, short- and long-term glutamatergic synaptic transmission was enhanced in PS-deficient neurons. Together, these results demonstrate for the first time that PS-mediated gamma-secretase activity attenuates receptor-mediated intracellular signaling pathways that are critical in regulating glutamatergic synaptic transmission and memory processes.

Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Carbamates; Carbazoles; Cell Adhesion Molecules; Cell Line, Tumor; Cell Membrane; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DCC Receptor; Dipeptides; Endopeptidases; Excitatory Postsynaptic Potentials; Genes, DCC; Glutamic Acid; Indoles; Lidocaine; Membrane Proteins; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neuroblastoma; Neurons; Piperazines; Presenilin-1; Protein Processing, Post-Translational; Pyrroles; Quinoxalines; Rats; Receptors, Cell Surface; Recombinant Fusion Proteins; Second Messenger Systems; Synaptic Transmission; Transfection; Tumor Suppressor Proteins