Synaptic plasticity is a key component of the learning machinery in the brain. It is vital that such plasticity be tightly regulated so that it occurs to the proper extent at the proper time. ...Activity-dependent mechanisms that have been collectively termed metaplasticity have evolved to help implement these essential computational constraints. Various intercellular signalling molecules can trigger lasting changes in the ability of synapses to express plasticity; their mechanisms of action are reviewed here, along with a consideration of how metaplasticity might affect learning and clinical conditions.
It has been 70 years since Donald Hebb published his formalized theory of synaptic adaptation during learning. Hebb's seminal work foreshadowed some of the great neuroscientific discoveries of the ...following decades, including the discovery of long-term potentiation and other lasting forms of synaptic plasticity, and more recently the residence of memories in synaptically connected neuronal assemblies. Our understanding of the processes underlying learning and memory has been dominated by the view that synapses are the principal site of information storage in the brain. This view has received substantial support from research in several model systems, with the vast majority of studies on the topic corroborating a role for synapses in memory storage. Yet, despite the neuroscience community's best efforts, we are still without conclusive proof that memories reside at synapses. Furthermore, an increasing number of non-synaptic mechanisms have emerged that are also capable of acting as memory substrates. In this review, we address the key findings from the synaptic plasticity literature that make these phenomena such attractive memory mechanisms. We then turn our attention to evidence that questions the reliance of memory exclusively on changes at the synapse and attempt to integrate these opposing views.
Activity-dependent synaptic plasticity phenomena such as long-term potentiation and long-term depression are candidate mechanisms for storing information in the brain. Regulation of synaptic ...plasticity is critical for healthy cognition and learning and this is provided in part by metaplasticity, which can act to maintain synaptic transmission within a dynamic range and potentially prevent excitotoxicity. Metaplasticity mechanisms also allow neurons to integrate plasticity-associated signals over time. Interestingly, astrocytes appear to be critical for certain forms of synaptic plasticity and metaplasticity mechanisms. Synaptic dysfunction is increasingly viewed as an early feature of AD that is correlated with the severity of cognitive decline, and the development of these pathologies is correlated with a rise in reactive astrocytes. This review focuses on the contributions of astrocytes to synaptic plasticity and metaplasticity in normal tissue, and addresses whether astroglial pathology may lead to aberrant engagement of these mechanisms in neurological diseases such as Alzheimer’s disease.
Glutamate receptors and metaplasticity in addiction Chiamulera, Cristiano; Piva, Alessandro; Abraham, Wickliffe C
Current opinion in pharmacology,
February 2021, 2021-Feb, 2021-02-00, 20210201, Letnik:
56
Journal Article
Recenzirano
•Metaplasticity phenomena underlie the state-dependency of synaptic plasticity.•Activation and trafficking of glutamate receptors underpin metaplasticity events.•Drug memory formation relies on ...metaplasticity effects in the reward system.•Metaplasticity mechanisms can also revert drug memory inflexibility.
Chronic drug use is a neuroadaptive disorder characterized by strong and persistent plasticity in the mesocorticolimbic reward system. Long-lasting effects of drugs of abuse rely on their ability to hijack glutamate receptor activity and long-term synaptic plasticity processes like long-term potentiation and depression. Importantly, metaplasticity-based modulation of synaptic plasticity contributes to durable neurotransmission changes in mesocorticolimbic pathways including the ventral tegmental area and the nucleus accumbens, causing ‘maladaptive’ drug memory and higher risk for drug-seeking relapse. On the other hand, drug-induced metaplasticity can make appetitive memories more malleable to modification, offering a potential target mechanism for intervention. Here we review the literature on the role of glutamate receptors in addiction-related metaplasticity phenomena.
Catastrophic forgetting (CF) refers to the sudden and severe loss of prior information in learning systems when acquiring new information. CF has been an Achilles heel of standard artificial neural ...networks (ANNs) when learning multiple tasks sequentially. The brain, by contrast, has solved this problem during evolution. Modellers now use a variety of strategies to overcome CF, many of which have parallels to cellular and circuit functions in the brain. One common strategy, based on metaplasticity phenomena, controls the future rate of change at key connections to help retain previously learned information. However, the metaplasticity properties so far used are only a subset of those existing in neurobiology. We propose that as models become more sophisticated, there could be value in drawing on a richer set of metaplasticity rules, especially when promoting continual learning in agents moving about the environment.
Catastrophic forgetting (CF) is the sudden and severe loss of memory for previously stored information due to the learning of new information. Standard artificial neural networks have traditionally suffered from CF when undertaking sequential learning tasks.A wide variety of strategies have been used to minimise forgetting, such as generative replay, constructive algorithms, complementary systems, sparse storage, and meta-learning.Metaplasticity is the activity-dependent plasticity of future plasticity or learning. Various network models use metaplasticity-type strategies to reduce forgetting during continual learning.Combining metaplasticity-type rules with other strategies often improves network performance even further.Models may benefit even more by drawing on other properties of biological metaplasticity phenomena.
Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity ...rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.
Highlights • A framework for potential roles of metaplasticity in vivo is presented. • Metaplasticity can prepare synapses and networks for learning. • Metaplasticity can homeostatically keep ...synaptic plasticity within a dynamic range. • Metaplasticity mechanisms may play roles in disease and treatment.
Adeno-associated viral (AAV) vectors are attractive tools for central nervous system (CNS) gene therapy because some vectors can cross the blood-brain barrier (BBB), allowing them to be used as ...minimally invasive treatments. A novel AAV vector recently evolved in vivo, AAV-PHP.eB, has been reported to cross the BBB more effectively than the existing gold standard AAV9, but not under all conditions. Here, we compared the efficacy of single-stranded AAV-PHP.eB and AAV9 in targeting mouse CNS and peripheral tissues after administration via various routes, in two different mouse strains (C57BL/6J and B6C3), and after packaging AAV-PHP.eB with a self-complementary genome. We found that AAV-PHP.eB produced higher CNS transduction than AAV9 after intravenous injection, but only in C57BL/6J and not in B6C3 mice. AAV-PHP.eB and AAV9 produced similar CNS transduction when the administration route did not require the vectors to cross the BBB. Packaging AAV-PHP.eB with a self-complementary genome increased overall CNS transduction, but at the expense of strong neuronal tropism. AAV-PHP.eB resulted in less transduction of liver tissue than AAV9 under all conditions. Taken together, these results suggest the potential for AAV-PHP.eB as a vector for CNS gene therapy applications, but consideration will be required for translation beyond mouse models.
Display omitted
Engineered AAV vector AAV-PHP.eB has improved ability over AAV9 to transduce mouse CNS after intravenous administration. Using various methods of administration, we show this is due to the increased ability of AAV-PHP.eB to cross the blood-brain barrier; however, this is dependent on the mouse strain used.
Long-term potentiation (LTP) is regulated in part by metaplasticity, the activity-dependent alterations in neural state that coordinate the direction, amplitude, and persistence of future synaptic ...plasticity. Previously, we documented a heterodendritic metaplasticity effect whereby high-frequency priming stimulation in stratum oriens (SO) of hippocampal CA1 suppressed subsequent LTP in the stratum radiatum (SR). The cytokine tumor necrosis factor (TNF) mediated this heterodendritic metaplasticity in wild-type rodents and in a mouse model of Alzheimer's disease. Here, we investigated whether LTP at other afferent synapses to CA1 pyramidal cells were similarly affected by priming stimulation. We found that priming stimulation in SO inhibited LTP only in SR and not in a second independent pathway in SO, nor in stratum lacunosum moleculare (SLM). Synapses in SR were also more sensitive than SO or SLM to the LTP-inhibiting effects of pharmacological TNF priming. Neither form of priming was sex-specific, while the metaplasticity effects were absent in TNFR1 knock-out mice. Our findings demonstrate an unexpected pathway specificity for the heterodendritic metaplasticity in CA1. That Schaffer collateral/commissural synapses in SR are particularly susceptible to such metaplasticity may reflect an important control of information processing in this pathway in addition to its sensitivity to neuroinflammation under disease conditions.
PDF
