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Hippocampal area CA2 has garnered attention in recent times owing to its significant involvement in social memory and distinctive plasticity characteristics. Research has revealed that the CA2 region demonstrates a remarkable resistance to plasticity, particularly in the Schaffer Collateral (SC)‐CA2 pathway. In this study we investigated the role of Nogo‐A, a well‐known axon growth inhibitor and more recently discovered plasticity regulator, in modulating plasticity within the CA2 region. The findings demonstrate that blocking Nogo‐A in male rat hippocampal slices facilitates the establishment of both short‐term and long‐term plasticity in the SC‐CA2 pathway, while having no impact on the Entorhinal Cortical (EC)‐CA2 pathway. Additionally, the study reveals that inhibiting Nogo‐A enables association between the SC and EC pathways. Mechanistically, we confirm that Nogo‐A operates through its well‐known co‐receptor, p75 neurotrophin receptor (p75NTR), and its downstream signaling factor such as Rho‐associated protein kinase (ROCK), as their inhibition also allows plasticity induction in the SC‐CA2 pathway. Additionally, the induction of long‐term depression (LTD) in both the EC and SC‐CA2 pathways led to persistent LTD, which was not affected by Nogo‐A inhibition. Our study demonstrates the involvement of Nogo‐A mediated signaling mechanisms in limiting synaptic plasticity within the CA2 region. [ABSTRACT FROM AUTHOR]

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve. Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activitydependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important. In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity. [ABSTRACT FROM AUTHOR]

The hippocampal CA2 region has received greater attention in recent years due to its fundamental role in social memory and hippocampus‐dependent memory processing. Unlike entorhinal cortical inputs, the Schaffer collateral inputs to CA2 do not support activity‐dependent long‐term potentiation (LTP), which serves as the basis for long‐term memories. This LTP‐resistant zone also expresses genes that restrict plasticity. With the aim of exploring social interaction and sociability in rats that were subjected to juvenile stress, we addressed questions about how the neural circuitry is altered and its effects on social behavior. Although there was induction of LTP in both Schaffer collateral and entorhinal cortical pathways in juvenile‐stressed rats, LTP declined in both pathways after 2–3 h. Moreover, exogenous bath application of substance P, a neuropeptide that resulted in slow onset long‐lasting potentiation in control animals while it failed to induce LTP in juvenile‐stressed rats. Our study reveals that juvenile‐stressed rats show behavioral and cellular abnormalities with a long‐lasting impact in adulthood. [ABSTRACT FROM AUTHOR]

The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC). Activation via NMDAR is critical for the induction of DA-LTP in both apical and basal dendrites, but only BDNF is required for the induction and maintenance of DA-LTP in apical dendrites. We report that dopaminergic modulation of LTP is lamina-specific at the Schaffer collateral/commissural synapses in the CA1 region.

Dopaminergic D1/D5-receptor-mediated processes are important for certain forms of memory as well as for a cellular model of memory, hippocampal long-term potentiation (LTP) in the CA1 region of the hippocampus. D1/D5-receptor function is required for the induction of the protein synthesis-dependent maintenance of CA1-LTP (L-LTP) through activation of the cAMP/PKA-pathway. In earlier studies we had reported a synergistic interaction of D1/D5-receptor function and N-methyl-D-aspartate (NMDA)-receptors for L-LTP. Furthermore, we have found the requirement of the atypical protein kinase C isoform, protein kinase M[zeta] (PKM[zeta]) for conventional electrically induced L-LTP, in which PKM[zeta] has been identified as a LTP-specific plasticity-related protein (PRP) in apical CA1-dendrites. Here, we investigated whether the dopaminergic pathway activates PKM[zeta]. We found that application of dopamine (DA) evokes a protein synthesis-dependent LTP that requires synergistic NMDA-receptor activation and protein synthesis in apical CA1-dendrites. We identified PKM[zeta] as a DA-induced PRP, which exerted its action at activated synaptic inputs by processes of synaptic tagging.

The protein synthesis-dependent form of hippocampal long-term potentiation (late-LTP) is thought to underlie memory. Its induction requires a distinct stimulation strength, and the common opinion is that only repeated tetani result in late-LTP whereas as single tetanus only reveals a transient early-LTP. Properties of LTP induction were compared to learning processes where repetition is often the prerequisite for a long-lasting memory. However, also single events can lead to manifested memory. If LTP subserves processes of learning, similar results should be detectable for LTP. Here we show that a single tetanus is sufficient to induce late-LTP requiring dopaminergic co-transmission during induction.

L-type CaV1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate CaV1.3 RNA editing, we demonstrate that unedited CaV1.3?ECS mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of CaV1.3 RNA editing sites slows Ca2+-dependent inactivation to increase Ca2+ influx but reduces channel open probability to decrease Ca2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited CaV1.3 channels permitted larger Ca2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the CaV1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the CaV1.3 channel in brain function. [ABSTRACT FROM AUTHOR]

Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyRmediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD. [ABSTRACT FROM AUTHOR]

The induction of long-lasting memory storage depends on the behavioral state of humans and animals. This behavioral state is mediated by neuromodulatory systems, like the cholinergic-septum-hippocampal circuit. Cholinergic neurotransmission is known to affect short-term activity-dependent plasticity in various brain areas, including the hippocampus. We could show here that a chemical late-long-term potentiation (LTP) could be induced in the basal dendrites by the coapplication of the cholinergic receptor agonist, carbachol, and the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram at a concentration that by itself has no effect on basal synaptic transmission. This chemical late-LTP was similar to electrical late-LTP in that it is dependent on protein synthesis, cAMP, and NMDA-receptor activation. Occlusion experiments demonstrated that saturation of three tetanus (TET) late-LTP occluded carbachol-rolipram-LTP, indicating that they share similar properties. This cholinergic modulation of LTP in the basal dendrites was mediated by both muscarinic and nicotinic receptors. Carbachol also reinforced an early form of LTP into a long-lasting LTP. Most interestingly, these two forms of LTP could participate in the functional plasticity processes like synaptic tagging and capture (STC). In addition, we studied whether a cooperation between cholinergic and glutamatergic receptors is essential to induce functional synaptic-plasticity. Indeed, we could show that coactivation of acetylcholine/PDE4 inhibition must coincide with the release of glutamate to induce a long-lasting plasticity, showing a functional convergence of the two neuromodulatory systems. Moreover, we could also show that both chemical late-LTP and carbachol-reinforced early-LTP-induced STC processes are mediated by the neurotrophin BDNF. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Protein synthesis-dependent forms of hippocampal long-term potentiation (late LTP) and long-term depression (late LTD) are prominent cellular mechanisms underlying memory formation. Recent data support the hypothesis that neurons store relevant information in dendritic functional compartments during late LTP and late LTD rather than in single synapses. It has been suggested that processes of "synaptic tagging" are restricted to such functional compartments. Here, we show that in addition to apical CA1 dendrites, synaptic tagging also takes place within basal CA1 dendritic compartments after LTP induction. We present data that tagging in the basal dendrites is restricted to these compartments. Plasticity-related proteins, partially nonspecific to the locally induced process, are synthesized in dendritic compartments and then captured by local, process-specific synaptic tags. We support these findings in two ways: (1) late LTP/LTD, locally induced in apical or basal (late LTP) dendrites of hippocampal CA1 neurons, does not spread to the basal or apical compartment, respectively; (2) the specificity of the synaptic plasticity event is achieved by the activation of process- and compartment-specific synaptic tag molecules. We have identified calcium/calmodulin-dependent protein kinase II as the first LTP-specific and extracellular signal-regulated kinase ½ as LTD-specific tag molecules in apical dendritic CA1 compartments, whereas either protein kinase A or protein kinase Mζ mediates LTP-specific tags in basal dendrites. [ABSTRACT FROM AUTHOR]

Rolipram, a selective inhibitor of cAMP-specific phosphodiesterase 4 (PDE4), has been shown to reinforce an early form of long-term potentiation (LTP) to a long-lasting LTP (late LTP). Furthermore, it was shown that the effects of rolipram-mediated reinforcement of LTP interacts with processes of synaptic tagging (Navakkode et al., 2004). Here we show in CA1 hippocampal slices from adult rats in vitro that rolipram also converted an early form of long-term depression (LTD) that normally decays within 2-3 h, to a long-lasting LTD (late LTD) if rolipram was applied during LTD-induction. Rolipram-reinforced LTD (RLTD) was NMDA receptor- and protein synthesis-dependent. Furthermore, it was dependent on the synergistic coactivation of dopaminergic D1 and D5 receptors. This let us speculate that RLTD resembles electrically induced, conventional CA1 late LTD, which is characterized by heterosynaptic processes and synaptic tagging. We therefore asked whether synaptic tagging occurs during RLTD. We found that early LTD in an S1 synaptic input was transformed into late LTD if early LTD was induced in a second independent S2 synaptic pathway during the inhibition of PDE by rolipram, supporting the interaction of processes of synaptic tagging during RLTD. Furthermore, application of PD 98059 (2′-amino-3′-methoxyflavone) or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), specific inhibitors of mitogen-activated protein kinases (MAPKs), prevented RLTD, suggesting a pivotal role of MAPK activation for RLTD. This MAPK activation was triggered during RLTD by the synergistic interaction of NMDA receptor- and D1 and D5 receptor-mediated Rap/B-Raf pathways, but not by the Ras/Raf-1 pathway in adult hippocampal CA1 neurons, as shown by the use of the pathway-specific inhibitors manumycin (Ras/Raf-1) and lethal toxin 82 (Rap/B-Raf). [ABSTRACT FROM AUTHOR]

Protein kinase Mζ (PKMζ) is a persistently active protein kinase C isoform that is synthesized during long-term potentiation (LTP) and is critical for maintaining LTP. According to "synaptic tagging," newly synthesized, functionally important plasticity-related proteins (PRPs) may prolong potentiation not only at strongly tetanized pathways, but also at independent, weakly tetanized pathways if synaptic tags are set. We therefore investigated whether PKMζ is involved in tagging and contributes to a sustained potentiation by providing strong and weak tetanization to two independent pathways and then disrupting the function of the kinase by a selective myristoylated ζ-pseudosubstrate inhibitory peptide. We found that persistent PKMζ activity maintains potentiated responses, not only of the strongly tetanized pathway, but also of the weakly tetanized pathway. In contrast, an independent, nontetanized pathway was unaffected by the inhibitor, indicating that the function of PKMζ was specific to the tagged synapses. To further delineate the specificity of the function of PKMζ in synaptic tagging, we examined synaptic "cross-tagging," in which late LTP in one input can transform early into late long-term depression (LTD) in a separate input or, alternatively, late LTD in one input can transform early into late LTP in a second input, provided that the tags of the weak inputs are set. Although the PKMζ inhibitor reversed late LTP, it did not prevent the persistent depression at the weakly stimulated, cross-tagged LTD input. Conversely, although the agent did not reverse late LTD, it blocked the persistent potentiation of weakly tetanized, cross-tagged synapses. Thus, PKMζ is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and cross-tagging. [ABSTRACT FROM AUTHOR]

We investigated the effects of rolipram, a selective cAMP phosphodiesterase (PDE) inhibitor, on late plastic events during functional CA1 plasticity in vitro in rat hippocampal slices. We present data showing that an early form of long-term potentiation (LTP) (early-LTP) that normally decays within 2-3 hr can be converted to a lasting LTP (late-LTP) if rolipram is applied during tetanization. This rolipram-reinforced LTP (RLTP) was NMDA receptor and protein synthesis dependent, cAMP formation in region CA1 during late-LTP requires dopaminergic receptor activity (Frey et al., 1989, 1990). Thus, we studied whether RLTP was influenced by inhibitors of the D1/D5 receptor. Application of the specific D1/D5 antagonist SCH23390 (0.1 µM) did not prevent RLTP, suggesting that the phosphodiesterase inhibitor acts downstream of the D1/D5 receptors. We also studied whether rolipram can interact with processes of synaptic tagging, because RLTP was also dependent on protein synthesis, similar to late-LTP. Inhibition of PDE and subsequent induction of RLTP in one synaptic population were able to transform early-LTP into late-LTP in a second, independent synaptic population of the same neurons. This supports our hypothesis that cAMP-dependent processes are directly involved in the synthesis of plasticity-related proteins. [ABSTRACT FROM AUTHOR]