title: Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent.
abstract: Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability. We examined the cLTP induced in acute slices by application of Sp-cAMPS or a combination of the adenylyl cyclase activator, forskolin, and the phosphodiesterase inhibitor, rolipram. Under our conditions, cLTP was induced but only if inhibition was reduced. We found that this form of cLTP was blocked by a N-methyl-d-aspartate receptor (NMDAR) antagonist and required the low-frequency test stimulation typically used to monitor the strength of synapses. Interestingly, similar LTP could be induced by lowering the Mg(2+) concentration of the ACSF during forskolin/rolipram or Sp-cAMPS application or even by just lowering Mg(2+) concentration alone. This LTP was also NMDAR dependent and required only a few ( approximately 5) low-frequency stimuli for its induction. The finding that even low-frequency synaptic stimulation was sufficient for LTP induction indicates that a highly sensitized plasticity state was generated. The fact that some stimulation was required means that potentiation is probably restricted to the stimulated axons, limiting the usefulness of this form of cLTP. However, when similar experiments were conducted using slice cultures, potentiation occurred without test stimuli, probably because the CA3-CA1 connections are extensive and because presynaptic spontaneous activity is sufficient to fulfill the activity requirement. As in acute slices, the potentiation was blocked by an NMDAR antagonist. Our general conclusion is that the induction of LTP caused by elevating cAMP requires presynaptic activity and NMDA channel opening. The method of inducing cLTP in slice cultures will be useful when it is desirable to produce NMDAR-dependent LTP in a large fraction of synapses.
authors.affiliation: Brandeis University, Volen Center For Complex Systems, Waltham, Massachusetts 02454, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Otmakhov
authors.forename: Lena
authors.initials: L
authors.lastname: Khibnik
authors.forename: Nonna
authors.initials: N
authors.lastname: Otmakhova
authors.forename: Stephen
authors.initials: S
authors.lastname: Carpenter
authors.forename: Shervin
authors.initials: S
authors.lastname: Riahi
authors.forename: Brent
authors.initials: B
authors.lastname: Asrican
authors.forename: John
authors.initials: J
authors.lastname: Lisman
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008274:Magnesium / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects
chemical_list: D005576:Colforsin; D000242:Cyclic AMP; D018756:GABA Antagonists; D008274:Magnesium; D010726:Phosphodiesterase Inhibitors; D010852:Picrotoxin; D016194:Receptors, N-Methyl-D-Aspartate; D020889:Rolipram