RESEARCH Examination of the Role of cGMP in Long-term Potentiation in the CA I Region of the Hippocampus

The mechan isms under ly ing the generat ion of NMDA receptor-dependent LTP in the CA1 region of the h ippocampus cont inue to receive a great deal of attention because of the postulated importance of LTP as a synaptic mechan ism for learning and memory. It is well accepted that the initial induct ion of LTP occurs in the postsynaptic cell, but the site of express ion remains controversial. One prominent hypothesis is that LTP involves the release of one or more retrograde messengers that act on the presynaptic terminal to enhance transmitter release. Recently, evidence has been presented that retrograde messengers funct ion to activate presynaptic guanylyl cyclase and that the result ing rise in presynaptic GMP levels, when accompanied by presynaptic activity, is responsible for generat ing an early component of LTP. We have tested this hypothes is by examining whether synaptic strength is increased by coupl ing tetanic st imulat ion with appl ication of a membrane-permeab le analog of cGMP. The exper iments were done in the presence of an NMDA receptor antagonist to b lock postsynaptic induct ion mechanisms. Under a variety of 6Corresponding author. exper imental condit ions, this manipu lat ion failed to generate LTP, suggest ing that an increase in cGMP levels accompanied by presynaptic activity is not sufficient o generate LTP in the CA1 region of the h ippocampus