Locus Ceruleus Activation Initiates Delayed Synaptic Potentiation of Perforant Path Input to the Dentate Gyrus in Awake Rats: A Novel β-Adrenergic- and Protein Synthesis-Dependent Mammalian Plasticity Mechanism

Abstract

Norepinephrine, acting through beta-adrenergic receptors, is implicated in mammalian memory. In in vitro and in vivo studies, norepinephrine produces potentiation of the perforant path-dentate gyrus evoked potential; however, the duration and dynamics of norepinephrine-induced potentiation have not been explored over extended time periods. To characterize the long-term effects of norepinephrine on granule cell plasticity, the present study uses glutamatergic activation of the locus ceruleus (LC) to induce release of norepinephrine in the hippocampus of the awake rat and examines the subsequent modulation of the dentate gyrus evoked potential for 3 hr (short term) and 24 hr (long term) after LC activation. LC activation initiates a potentiation of the field EPSP slope observed 24 hr later. This late-phase potentiation of the synaptic potential is not preceded by early phase potentiation, although spike potentiation can be seen both immediately after, and 24 hr after, LC activation. Intracerebroventricular infusion of the beta-adrenergic antagonist, propranolol, or the protein synthesis inhibitor, anisomycin, before LC activation blocks the potentiation of perforant path input observed at 24 hr. The initiation of late-phase synaptic potentiation observed at 24 hr but not at the 3 hr after LC activation parallels the observation of a cAMP- and protein synthesis-dependent long-lasting synaptic facilitation in Aplysia that is not preceded by short-term synaptic facilitation. Locus ceruleus-initiated synaptic potentiation may selectively support long-term, rather than short-term, memory. The observation of selective initiation of long-term synaptic facilitation in a mammalian brain, as in invertebrates, is additional evidence that these two forms of memory depend on separable biological mechanisms.