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The master epigenetic regulator lysine acetyltransferase (KAT) p300/CBP plays a pivotal role in neuroplasticity and cognitive functions. Recent evidence has shown that in several neurodegenerative diseases, including Alzheimer's disease (AD), the expression level and function of p300/CBP are severely compromised, leading to altered gene expression causing pathological conditions. Here, we show that p300/CBP activation by a small‐molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ‐impaired long‐term potentiation (LTP) induced by high‐frequency stimulation, theta burst stimulation, and synaptic tagging/capture (STC). This functional rescue was correlated with CSP‐TTK21‐induced changes in transcription and translation. Mechanistically, we observed that the expression of a large number of synaptic plasticity‐ and memory‐related genes was rescued, presumably by the restoration of p300/CBP mediated acetylation. Collectively, these results suggest that small‐molecule activators of p300/CBP could be a potential therapeutic molecule for neurodegenerative diseases like AD. Exogenous Aß(1–42) oligomers impair high‐frequency stimulation‐ and dopaminergic agonist‐induced synaptic plasticity and associative plasticity in the rat hippocampal area CA1. CSP‐TTK21, a small‐molecule activator of lysine acetyltransferase CBP/p300, rescues such Aß‐impaired synaptic plasticity. CSP‐TTK21 changes the transcriptome of area CA1 of Aß‐treated rat hippocampal slices and rescues the expression of key plasticity‐related proteins (PRPs).

The hippocampus is a critical brain region for the formation of declarative memories. While social memory had long been attributed to be a function of the hippocampus, it is only of late that the area CA2 of the hippocampus was demarcated as essential for social memory formation. In addition to this distinct role, CA2 possesses unique molecular, structural and physiological characteristics compared to the other CA regions—CA1 and CA3, and the dentate gyrus (DG). CA2 pyramidal neurons are positioned at a location between CA1 and CA3, receiving inputs from CA3 and DG, in addition to forming a powerful disynaptic circuit with direct input from the entorhinal cortical layer II neurons. CA2 also receives direct inputs from the hypothalamic regions and displays a unique expression pattern for receptors for neuromodulators. The location, inputs, and molecular signatures of the area CA2 point to the possibility that CA2 serves as a modulatory gateway that processes information from the entorhinal cortex and CA3, before relaying them onto CA1, the major output of the hippocampus. This review discusses recent findings regarding plasticity and neuromodulation in the CA2 region of the hippocampus, and how this may have the potential to influence plasticity in connecting circuits, and thereby memory and behaviour.

Most elementary behaviors such as moving the arm to grasp an object or walking into the next room to explore a museum evolve on the time scale of seconds; in contrast, neuronal action potentials occur on the time scale of a few milliseconds. Learning rules of the brain must therefore bridge the gap between these two different time scales. Modern theories of synaptic plasticity have postulated that the co-activation of pre- and postsynaptic neurons sets a flag at the synapse, called an eligibility trace, that leads to a weight change only if an additional factor is present while the flag is set. This third factor, signaling reward, punishment, surprise, or novelty, could be implemented by the phasic activity of neuromodulators or specific neuronal inputs signaling special events. While the theoretical framework has been developed over the last decades, experimental evidence in support of eligibility traces on the time scale of seconds has been collected only during the last few years. Here we review, in the context of three-factor rules of synaptic plasticity, four key experiments that support the role of synaptic eligibility traces in combination with a third factor as a biological implementation of neoHebbian three-factor learning rules.

The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal‐dependent long‐term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age‐related decline. The p75 neurotrophin receptor (p75NTR) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age‐related alterations. However, the mechanisms by which p75NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75NTR were resistant to age‐associated changes in long‐term plasticity, associative plasticity, and associative memory. Our study shows that p75NTR is responsible for age‐dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA‐ROCK2‐LIMK1‐cofilin. p75NTR may thus represent an important therapeutic target for limiting the age‐related memory and cognitive function deficits. This cartoon depicts the signaling pathway by p75NTR in mediating synaptic plasticity changes in aging. Aging increases proBDNF without affecting mature BDNF. ProBDNF has been implicated in facilitating LTD. Aging also modulates MAPK pathway by upregulating p38 activity while downregulating ERK1/2 activity. Both p38 and ERK1/2 pathways are important in regulating Arc gene transcription. Aging decreases Arc protein, thus affecting the maintenance of LTP and LTM consolidation through regulation of actin dynamics. In addition, aging increases RhoA level leading to an increase in ROCK2 activity. This reduces both LIMK1 and cofilin phosphorylation. Modulation of cofilin activity is essential for the reorganization of the actin cytoskeleton and influences synaptic plasticity. As a whole, p75NTR is responsible for the age‐mediated disruption of hippocampal homeostatic long‐term plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA‐ROCK2‐LIMK1‐cofilin, leading to deficits in STC and associative memory. Red arrow indicates increases. Green arrow indicates decreases. Orange equals sign indicates no change.

Clinical studies have shown that female brains are more predisposed to neurodegenerative diseases such as Alzheimer's disease (AD), but the cellular and molecular mechanisms behind this disparity remain unknown. In several mouse models of AD, synaptic plasticity dysfunction is an early event and appears before significant accumulation of amyloid plaques and neuronal degeneration. However, it is unclear whether sexual dimorphism at the synaptic level contributes to the higher risk and prevalence of AD in females. Our studies on APP/PS1 (APPSwe/PS1dE9) mouse model show that AD impacts hippocampal long‐term plasticity in a sex‐specific manner. Long‐term potentiation (LTP) induced by strong tetanic stimulation (STET), theta burst stimulation (TBS) and population spike timing‐dependent plasticity (pSTDP) show a faster decay in AD females compared with age‐matched AD males. In addition, behavioural tagging (BT), a model of associative memory, is specifically impaired in AD females with a faster decay in memory compared with males. Together with the plasticity and behavioural data, we also observed an upregulation of neuroinflammatory markers, along with downregulation of transcripts that regulate cellular processes associated with synaptic plasticity and memory in females. Immunohistochemistry of AD brains confirms that female APP/PS1 mice carry a higher amyloid plaque burden and have enhanced microglial activation compared with male APP/PS1 mice. Their presence in the diseased mice also suggests a link between the impairment of LTP and the upregulation of the inflammatory response. Overall, our data show that synaptic plasticity and associative memory impairments are more prominent in females and this might account for the faster progression of AD in females. Sex‐specific study of synaptic plasticity and memory reveals female APP/PS1 mice carry a higher amyloid plaque burden and enhanced Iba‐1‐positive microglial activation compared with male APP/PS1. In addition, synaptic plasticity and associative memory impairments are also more prominent in females than in males.

Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long‐term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aβ (1–42)‐induced AD condition. This study demonstrates that expression of miR‐134‐5p, a brain‐specific miRNA is upregulated in Aβ (1–42)‐treated AD hippocampus. Interestingly, the loss of function of miR‐134‐5p restored late LTP and STC in AD. In AD brains, inhibition of miR‐134‐5p elevated the expression of plasticity‐related proteins (PRPs), cAMP‐response‐element binding protein (CREB‐1) and brain‐derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR‐134‐mediated post‐transcriptional regulation of CREB‐1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR‐134‐5p as a potential therapeutic target for restoring plasticity in AD condition. Late long‐term potentiation (late LTP) and synaptic tagging and capture (STC) are impaired in Aβ (1–42)‐treated AD hippocampus. miR‐134‐5p expression is significantly upregulated in AD hippocampus which induces impairment in late LTP and STC by post‐transcriptionally regulating the expression of plasticity‐related genes CREB‐1 and BDNF. Inhibition of miR‐134‐5p using miR‐134‐5p specific antagomir (miR‐134i) upregulates the expression of CREB‐1 and BDNF which is otherwise downregulated in AD thereby, reinstating late LTP and STC in AD hippocampus.

The hippocampal area Cornu Ammonis (CA) CA2 is important for social interaction and is innervated by Substance P (SP)-expressing supramammillary (SuM) nucleus neurons. SP exerts neuromodulatory effects on pain processing and central synaptic transmission. Here we provide evidence that SP can induce a slowly developing NMDA receptor- and protein synthesis-dependent potentiation of synaptic transmission that can be induced not only at entorhinal cortical (EC)-CA2 synapses but also at long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. In addition, SP-induced potentiation of SC-CA2 synapses transforms a short-term potentiation of EC-CA2 synaptic transmission into LTP, consistent with the synaptic tagging and capture hypothesis. Interestingly, this SP-induced potentiation and associative interaction between the EC and SC inputs of CA2 neurons is independent of the GABAergic system. In addition, CaMKIV and PKMζ play a critical role in the SP-induced effects on SC-CA2 and EC-CA2 synapses. Thus, afferents from SuM neurons are ideally situated to prime CA2 synapses for the formation of long-lasting plasticity and associativity.

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 RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.

In spike-timing-dependent plasticity (STDP), the direction and degree of synaptic modification are determined by the coherence of pre- and postsynaptic activities within a neuron. However, in the adult rat hippocampus, it remains unclear whether STDP-like mechanisms in a neuronal population induce synaptic potentiation of a long duration. Thus, we asked whether the magnitude and maintenance of synaptic plasticity in a population of CA1 neurons differ as a function of the temporal order and interval between pre- and postsynaptic activities. Modulation of the relative timing of Schaffer collateral fibers (presynaptic component) and CA1 axons (postsynaptic component) stimulations resulted in an asymmetric population STDP (pSTDP). The resulting potentiation in response to 20 pairings at 1 Hz was largest in magnitude and most persistent (4 h) when presynaptic activity coincided with or preceded postsynaptic activity. Interestingly, when postsynaptic activation preceded presynaptic stimulation by 20 ms, an immediate increase in field excitatory postsynaptic potentials was observed, but it eventually transformed into a synaptic depression. Furthermore, pSTDP engaged in selective forms of late-associative activity: It facilitated the maintenance of tetanization-induced early long-term potentiation (LTP) in neighboring synapses but not early long-term depression, reflecting possible mechanistic differences with classical tetanization-induced LTP. The data demonstrate that a pairing of pre- and postsynaptic activities in a neuronal population can greatly reduce the required number of synaptic plasticity-evoking events and induce a potentiation of a degree and duration similar to that with repeated tetanization. Thus, pSTDP determines synaptic efficacy in the hippocampal CA3–CA1 circuit and could bias the CA1 neuronal population toward potentiation in future events.

The localization of RNAs critically contributes to many important cellular processes in an organism, such as the establishment of polarity, asymmetric division and migration during development. Moreover, in the central nervous system, the local translation of mRNAs is thought to induce plastic changes that occur at synapses triggered by learning and memory. Here, we will critically review the physiological functions of well‐established dendritically localized mRNAs and their associated factors, which together form ribonucleoprotein particles (RNPs). Second, we will discuss the life of a localized transcript from transcription in the nucleus to translation at the synapse and introduce the concept of the ‘ RNA signature ’ that is characteristic for each transcript. Finally, we present the ‘ sushi belt model ’ of how localized RNAs within neuronal RNPs may dynamically patrol multiple synapses rather than being anchored at a single synapse. This new model integrates our current understanding of synaptic function ranging from synaptic tagging and capture to functional and structural reorganization of the synapse upon learning and memory. In this review, our understanding of the mechanisms and regulation of dendritic mRNA localization is synthesized into a ‘sushi belt’ model of mRNA transport and translational control in neurons.