Beta-adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus

Abstract

Activation of beta-adrenergic receptors (beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms of long-lasting hippocampal LTP. How does beta-AR activation affect the PKA-dependence, and persistence, of LTP elicited by distinct stimulation frequencies? Here, we use in vitro electrophysiology to show that patterns of stimulation determine the temporal phase of LTP affected by beta-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following beta-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of beta-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of beta-ARs can gate the PKA-dependence and persistence of synaptic plasticity. We suggest that this may allow neuromodulatory receptors to fine-tune neural information processing to meet the demands imposed by numerous synaptic activity profiles. This is a form of "metaplasticity" that could control the efficacy of consolidation of hippocampal long-term memories.

Figure 1.

Activation of β-adrenergic receptors rescues impairments of LTP maintenance generated by genetic PKA deficiency. (A) In wild-type mice, application of ISO does not alter LTP generated by four trains of HFS. (B) In mutant mice, maintenance of LTP generated by four trains of LTP is impaired. Application of ISO significantly enhances the maintenance of this LTP. (C) Summary histogram showing that initial potentiation levels are not affected by application of ISO during four trains of HFS in wild-type or mutant mice. (D) Summary histogram showing that the maintenance of LTP is significantly enhanced by ISO application in mutant mice only (*P < 0.05). All sample traces were taken 10 min after commencement of baseline recording and 120 min after HFS. Calibration: 5 mV, 2 msec.

Figure 2.

Activation of β-adrenergic receptors abolishes impairments of LTP maintenance generated by pharmacologic PKA deficiency. (A) Four trains of HFS generate long-lasting LTP. (B) Application of KT5720 causes LTP elicited by four trains of HFS to decay to levels significantly below KT5720-free controls. Application of ISO enhances the maintenance of this LTP. (C) Summary histogram for these experiments (*P < 0.05, **P < 0.01). All sample traces were taken 10 min after commencement of baseline recording and 120 min after HFS. Calibration: 5 mV, 2 msec.

Figure 3.

Slices from R(AB) mice exhibit intact β-adrenergic receptor-dependent enhancement of LTP maintenance. (A) In slices from wild-type mice, application of ISO during one train of HFS induces long-lasting LTP, whereas one train of HFS alone induces decremental LTP. (B) Application of ISO during one train of HFS in mutant slices similarly induces long-lasting LTP. (C) Summary histogram for these experiments comparing levels of potentiation 5 min after HFS. (D) Summary histogram for these experiments comparing levels of potentiation 120 min after HFS (*P < 0.05). All sample traces were taken 10 min after commencement of baseline recording and 120 min after HFS. Calibration: 5 mV, 2 msec.

Figure 4.

β-Adrenergic receptor-dependent enhancement of LTP maintenance does not require PKA. (A) Application of KT5720 does not inhibit maintenance of LTP elicited by pairing ISO with one train of HFS. (B) Application of Rp does not inhibit maintenance of LTP elicited by pairing ISO with HFS. (C) Similarly, application of PKI does not inhibit maintenance of LTP elicited by pairing ISO with HFS. (D) Summary histogram for these experiments comparing levels of potentiation 120 min after HFS. All sample traces were taken 10 min after commencement of baseline recording and 120 min after HFS. Calibration: 5 mV, 2 msec.

Figure 5.

Induction of β-adrenergic receptor-dependent LTP generated by LFS is inhibited by genetic reduction of PKA activity. (A) In slices from wild-type mice, pairing ISO with LFS generates robust LTP. (B) In slices from mutant R(AB) mice, induction of this LTP is significantly decreased. (C) Summary histogram for these experiments comparing levels of potentiation 15 min after LFS (*P < 0.05). All sample traces were taken 10 min after commencement of baseline recording and 15 min after LFS. Calibration: 5 mV, 2 msec.

Figure 6.

β-Adrenergic receptor-dependent enhancement of LTP induction during LFS requires PKA and mTOR. (A) Application of ISO during LFS induces long-lasting LTP. Co-application of KT5720 significantly blunts induction of this LTP. (B) Co-application of Rap completely blocks induction of this LTP. (C) APV, an NMDA receptor blocker, significantly attenuated expression of this LTP. (D) Summary histogram for these experiments comparing potentiation levels 15 min after LFS (*P < 0.05, **P < 0.01). All sample traces were taken 10 min after commencement of baseline recording and 15 min after LFS. Calibration: 5 mV, 2 msec.

Figure 7.

β-Adrenergic receptor-dependent enhancement of complex spiking requires NMDA receptor activation but not PKA or mTOR signaling. (A) In control slices, 3 min of 5-Hz stimulation (LFS) elicits a modest amount of complex spiking. (B) In the presence of ISO (1 μM), complex spiking was increased significantly. (C) Treatment with KT5720, a PKA inhibitor, did not significantly alter the numbers of complex spikes elicited during LFS in ISO. (D) Rapamycin, an mTOR inhibitor, also did not significantly alter total numbers of spikes. (E) APV significantly reduced the total numbers of complex spikes elicited during LFS. See Results section for mean values of total spike numbers. (F) Summary histogram of total numbers of complex spikes elicited during LFS in these conditions (*P < 0.05, **P < 0.01). Numbers of spikes were counted from individual fEPSP sweeps across the 3-min period of LFS.