Hippocampal long-term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta-adrenoreceptors and the locus coeruleus

Abstract

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus-based learning, and facilitates synaptic plasticity in the form of long-term depression (LTD) and long-term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β-adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β-adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β-adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant-path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β-adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β-adrenoreceptor-antagonism also prevented spatial learning. Strikingly, activation of the LC before high-frequency stimulation (HFS) of the pp prevented short-term potentiation but not LTP, and LC stimulation after pp-HFS-induced depotentiation of LTP. This depotentiation was prevented by β-adrenoreceptor-antagonism. These data suggest that β-adrenoreceptor-activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus.

Keywords: beta-adrenergic receptors; hippocampus; learning-facilitated long-term potentiation; long-term potentiation; rat.

Figure 1

Long‐term potentiation that is induced in the dentate gyrus by patterned stimulation of the perforant path requires β‐adrenoreceptor activation. (A, B) Weak high frequency stimulation (wHFS; 100 Hz) causes short‐term potentiation in the dentate gyrus (DG) that lasts for less than 1 h. (D, E) High frequency stimulation (HFS, 10 trains at 200 Hz) induces long‐term potentiation (LTP) in the DG that lasts for over 24 h. Prior treatment with the ß‐adrenoreceptor antagonist propranolol (2 µg) significantly attenuates this LTP. The mean population spike (PS) amplitude (A, D) and mean fEPSP slope (B, E) are shown along with the corresponding standard error of the mean (SEM). (C) Analog traces represent perforant path‐DG field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle and test‐pulse stimulation, or (iv) 5 min before, (v) 5 min after and (vi) 24 h after vehicle and weak HFS stimulation. (F) Analog traces represent perforant path‐DG field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of HFS stimulation, or (iv) 5 min before, (v) 5 min after and (vi) 24 h after propranolol in the presence of HFS stimulation. Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 2

Long‐term potentiation is facilitated by activating β‐adrenoreceptors in the dentate gyrus. (A, B) Subthreshold‐high frequency stimulation (sub‐HFS, three trains at 200 Hz) elicits short‐term potentiation (STP) that lasts about 3 h in vehicle‐treated animals. Prior treatment with the ß‐adrenoreceptor agonist isoproterenol (20 µg) facilitates STP into LTP that endures for at least 25 h (A, B). (C) Analog traces represent perforant path‐dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of sHFS, or (iv) 5 min before, (v) 5 min after, and (vi) and 24 h after isoproterenol in the presence of sHFS. Calibration: Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 3

Locus coeruleus stimulation before weak high‐frequency stimulation prevents short‐term potentiation of perforant path‐dentate gyrus synapses. (A, B) Locus coeruleus (LC) stimulation leads to long‐term depression (LTD) in the dentate gyrus (DG) compared with test‐pulse stimulated controls. When LC stimulation was applied before weak high‐frequency stimulation (wHFS) (100 Hz), short‐term potentiation (STP) was significantly impaired (D, E). By 24 h after LC stimulation, LTD was apparent compared with animal that received wHFS only. (C) Analog traces represent perforant path‐dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of test pulse stimulation, or (iv) 5 min before, (v) 5 min after, and (vi) and 24 h after vehicle in the presence of LC stimulation. (F) Analog traces represent perforant path dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of HFS, or (iv) 5 min before, (v) 5 min after, and (vi) and 24 h after vehicle in the presence of prior LC stimulation to HFS. Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 4

Long‐term potentiation of perforant path‐dentate gyrus synapses is depotentiated by subsequent, but not antecedent, locus coeruleus stimulation. (A, B) Strong high frequency stimulation (HFS: 10 trains at 200 Hz) induces long‐term potentiation (LTP) in dentate gyrus that lasts for over 25 h. Stimulation of the LC before HFS does not alter the profile of LTP. (D, E) LC stimulation after HFS results in significant depotentiation. Treatment with the ß‐adrenoreceptor antagonist propranolol (2 µg) before HFS/LC stimulation significantly prevents depotentation. (C) Analog traces represent perforant path‐dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of HFS or (iv) 5 min before, (v) 5 min after, and (vi) and 24 h after vehicle in the presence of LC stimulation before HFS. (F) Analog traces represent perforant path dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of HFS, (iv) 5 min before, (v) 5 min after, and (vi) and 24 h after vehicle in the presence of LC stimulation after HFS and (vii) 5 min before, (viii) 5 min after, and (ix) and 24 h after propranolol in the presence of LC stimulation after HFS. Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 5

Learning about a novel environment facilitates long‐term potentiation at perforant path‐dentate gyrus synapses. (A, B) Subthreshold‐high frequency stimulation (sub‐HFS, three trains at 200 Hz) elicits synaptic potentiation that lasts for over 2 h, but less than 3 h, in vehicle‐treated animals. Coupling sub‐HFS with exploration of a novel holeboard significantly prolongs STP, resulting in a long‐term potentiation (LTP) that lasts for over 25 h. Exposing the rats a second time to the now familiar holeboard does not result in LTP following sub‐HFS. The STP evoked is equivalent to control responses (see Fig. 2). (C) Analog traces represent perforant path‐dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after and (iii) 24 h after vehicle in the presence of sub‐HFS, (iv) 5 min before, (v) 5 min after and (vi) 24 h after novel holeboard exploration in the presence of sub‐HFS as well as (vii) 5 min before, (viii) 5 min after (ix) and 24 h after familiar holeboard exploration in the presence of sub‐HFS. Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 6

The facilitation of long‐term potentiation by novel spatial learning is prevented by a β‐adrenoreceptor antagonist. (A, C) Subthreshold‐high frequency stimulation (sub‐HFS, three trains at 200 Hz) elicits STP that last for less than 3 h in vehicle‐treated animals. Prior treatment with the ß‐adrenoreceptor antagonist propranolol (2 µg) inhibits the facilitation of LTP by exposure to a novel holeboard that typically occurs in vehicle‐treated controls (see Fig. 3). In contrast exposing the rats a second time to the now familiar holeboard facilitates LTP (B, D). This suggests that propranolol prevented spatial learning in conjunction with LTP (see Fig. 7). (E) Analog traces represent perforant path‐dentate gyrus (DG) field potentials (i) 5 min before, (ii) 5 min after, and (iii) 24 h after vehicle in the presence of sHFS, (iv) 5 min before, (v) 5 min after, and (vi) 24 h after propranolol in the presence of sHFS coupled with the novel holeboard exposure and (vii) 5 min before, (viii) 5 min after, and (ix) 24 h after vehicle in the presence of sHFS coupled with the second holeboard exposure. Vertical bar, 3 mV; horizontal bar, 2.5 ms.

Figure 7

Novel spatial learning is prevented by a β‐adrenoreceptor antagonist. The bar charts illustrate the mean number of rears in (A) or dips in (B) (nose‐pokes into holeboard holes) that occurred when the animals were exposed to the holeboard. The mean number of rears (A) and dips (B) is significantly lower when performance during holeboard re‐exposure (white bars) is compared with performance during novel exposure (black bars). Treatment with propranolol resulted in equivalent rearing (A) and dipping (B) behavior during novel and familiar holeboard exposure. Performance was equivalent to the behaviour of vehicle‐treated animals during novel holeboard exposure. This confirms that propranolol prevented learning of the spatial environment. t‐test: *P < 0.05.