Learning-facilitated long-term depression and long-term potentiation at mossy fiber—CA3 synapses requires activation of β-adrenergic receptors

Learning-facilitated plasticity refers to hippocampal synaptic plasticity that is facilitated by novel spatial learning events. Both long-term potentiation (LTP) and long-term depression (LTD) are facilitated by novel hippocampus-dependent learning. This has important ramifications for our understanding of how the hippocampus encodes memory. One structure that is rarely studied in vivo, but is believed to be crucially important for working and long-term memory processing is the hippocampal CA3 region. Whereas learning-facilitated plasticity has been described in this structure, the mechanisms underlying this phenomenon have not been explored. The noradrenergic system plays an important role in arousal and qualification of new information as salient. It regulates synaptic plasticity in the dentate gyrus and CA1, but nothing is known about the regulation by the noradrenergic system of synaptic plasticity in the CA3 region. We explored whether β-adrenergic receptors contribute to learning-facilitated plasticity at mossy fiber (mf)-CA3 synapses of behaving rats. We found that receptor antagonism had no effect on basal synaptic transmission, short-term potentiation (STP), short-term depression, LTP, or LTD, that were electrically induced by patterned afferent stimulation. We found, however, that both learning-facilitated LTP and LTD were prevented by antagonism of β-adrenergic receptors, whereas the agonist isoproterenol facilitated STP into LTP. Thus, learning-facilitated and electrically-induced plasticity may not share the same prerequisites. These results support that the mf synapse engages in a distinct aspect of encoding of spatial information that involves both LTP and LTD. Furthermore, changes in arousal that are coupled to new learning are associated with activation of hippocampal β-adrenergic receptors that in turn comprise a key element in this type of information acquisition and processing by the CA3 region

Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

Irreversible N-methyl-D-aspartate receptor (NMDAR) antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP) of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments.The ability to express long-term potentiation (LTP) at the perforant pathway – dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3 and 4 weeks after a single -treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue.Taken together, these data support that acute treatment with an irreversible NMDAR antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders

Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters

Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction in mice in the CA1 region has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7 or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g. 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g. learning) conditions

The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing

In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We established that field excitatory postsynaptic potentials at the pp-CA1 have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (> 24h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing

Involvement of dopamine D1/D5 and D2 receptors in context-dependent extinction learning and memory reinstatement

Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context ‘A’) to associate a goal arm with a food reward, despite low reward probability (acquisition phase). On day 4, extinction learning (unrewarded) occurred, that was reinforced by a context change (‘B’). On day 5, re-exposure to the (unrewarded) ‘A’-context took place (renewal of context ‘A’, followed by extinction of context ‘A’). In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal) on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context ‘B’. By contrast, a D1/D5-agonist impaired renewal in context ’A’. Extinction in the ‘A’ context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context ‘B or renewal in context ‘A’, although extinction of the renewal effect was impaired on day 5, compared to controls.Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning

Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

The noradrenergic (NA)-system is an important regulator of cognitive function. It contributes to extinction learning(EL), and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR), regulates EL that depends on context, but is not fear-associated. We assessed behaviour in an ‘AAA’ or ‘ABA’ paradigm: rats were trained for 3 days in a T-maze(context-A) to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL(unrewarded), whereby in the ABA-paradigm, EL was reinforced by a context change (B), and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded) occurred. Typically, in control ‘AAA’ animals EL occurred on day 4 that progressed further on day 5. In control ‘ABA’ animals, EL also occurred on day 4, followed by renewal of the previously learned (A) behavior on day 5, that was followed (in day 5) by extinction of this behavior, as the animals realised that no food reward would be given.Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the ‘ABA’ paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B). Furthermore, β-AR-antagonism prior to renewal testing (on day 5) in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the ‘A’ context.β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction learning in constant-context conditions

Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signalling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioural changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry