Heterosynaptic depression: a postsynaptic correlate of long-term potentiation

Lynch, Gary; Dunwiddie, Thomas V.; Gribkoff, Valentin K.

doi:10.1038/266737a0

Cited by 555 publications

(306 citation statements)

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“…Rather, the recruitment and synchronization of oscillatory networks is considered to be an emergent property of epileptic activity (Javitt and Coyle, 2004), which leaves open the question whether there might be a key regulator or endogenous inhibitor for the synchronization of neuronal networks. The concept of heterosynaptic depression was established 30 years ago by findings that high frequency stimulation of a particular excitatory pathway caused a depression of nearby pathways (Lynch et al, 1977). This could indeed be an endogenous mechanism to prevent synchronization of neuronal networks.…”

Section: Chronic Epilepsymentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Section: Chronic Epilepsymentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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“…This consists in the observation that a high frequency stimulation of a particular excitatory pathway causes a depression in nearby pathways (Lynch et al, 1977). When first described, this was proposed to depend on the recruitment on interneurons (Manzoni et al, 1994).…”

Section: Adenosine As a Hetero-synaptic Modulator-a 1 Receptorsmentioning

confidence: 99%

“…This was confirmed in a recent elegant study which established that the high frequency stimulation of a set of Schaffer fibers in hippocampal slices led to the sequential activation of NMDA receptors in GABAergic interneurons and the GABA released would trigger astrocytic activation through GABA B receptors (Kang et al, 1998;Serrano et al, 2006); thanks to the long-range propagation of Ca 2+ waves in astrocytic syncytium (up to 100 mm; reviewed in Halassa et al, 2007;Haydon and Carmignoto, 2006;Scemes and Giaume, 2006), the astrocytes could release ATP in sites facing distant non-stimulated synapses (Pascual et al, 2005;Serrano et al, 2006;Zhang et al, 2003), which, upon extracellular degradation by ecto-nucleotidases, would activate A 1 receptors in these distant non-stimulated synapses (Serrano et al, 2006). This heterosynaptic depression triggered in a group of neighbouring excitatory synapses as a result of the highfrequency stimulation of a particular synapse has an important physiological role: it is designed to increase contrast between activated synapses undergoing plastic changes and nontetanised synapses (Lynch et al, 1977;Serrano et al, 2006). One expected correlate is that the decrease of this A 1 receptormediated heterosynaptic depression might facilitate synchronization of neuronal activity, which has been proposed to cause seizures (see Halassa et al, 2007).…”

Section: Adenosine As a Hetero-synaptic Modulator-a 1 Receptorsmentioning

confidence: 99%

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

Cunha

2008

Neurochemistry International

148

129

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Adenosine is a prototypical neuromodulator, which mainly controls excitatory transmission through the activation of widespread inhibitory A 1 receptors and synaptically located A 2A receptors. It was long thought that the predominant A 1 receptor-meditated modulation by endogenous adenosine was a homeostatic process intrinsic to the synapse. New studies indicate that endogenous extracellular adenosine is originated as a consequence of the release of gliotransmitters, namely ATP, which sets a global inhibitory tonus in brain circuits rather than in a single synapse. Thus, this neuron-glia long-range communication can be viewed as a form of non-synaptic transmission (a concept introduced by Professor Sylvester Vizi), designed to reduce noise in a circuit. This neuron-glia-induced adenosine release is also responsible for exacerbating salient information through A 1 receptor-mediated heterosynaptic depression, whereby the activation of a particular synapse recruits a neuron-glia network to generate extracellular adenosine that inhibits neighbouring non-tetanised synapses. In parallel, the local activation of facilitatory A 2A receptors by adenosine, formed from ATP released only at high frequencies from neuronal vesicles, down-regulates A 1 receptors and facilitates plasticity selectively in the tetanised synapse. Thus, upon high-frequency firing of a given pathway, the combined exacerbation of global A 1 receptormediated inhibition in the circuit (heterosynaptic depression) with the local synaptic activation of A 2A receptors in the activated synapse, cooperate to maximise salience between the activated and non-tetanised synapses. #

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“…26,51 The other is long-term depression (LTD), which was originally seen in the CA1 field of the hippocampus as a heterosynaptic correlate of the homosynaptic LTP in this field. 34 Later, heterosynaptic LTD was also seen in the dentate gyrus, 1,30,31 and homosynaptic form of LTD was found in the CA1 field of the hippocampus 14,37 and elsewhere in the brain. 32 Originally, LTP was induced by brief (1-2 s) highfrequency (50-100 Hz) stimulation (HFS) of afferent fibres.…”

mentioning

confidence: 99%

Increasing age reduces expression of long-term depression and dynamic range of transmission plasticity in CA1 field of the rat hippocampus

et al. 1998

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Abstract--Long-term depression, depotentiation and long-term potentiation of field excitatory postsynaptic potentials in the CA1 field of the hippocampus were studied in slices from two-, 12-, 24-and 36-week-old rats. Long-term potentiation was induced by stimulating afferent fibres for 1 s at 100 Hz. Long-term depression was induced either by stimulating the afferent pathways twice for 15 min at 1 Hz (protocol 1), giving in total 1800 pulses, or by stimulating the fibres at 5 min intervals twice at 1 Hz for 5 min followed by 5 min stimulation at 5 Hz (protocol 2), giving in total 2100 pulses. We found significant long-term depression in slices of all groups stimulated with protocol 1; however, the magnitude of long-term depression in slices from 24-and 36-week-old rats was significantly lower than that in slices from two-and 12-week old rats, although there was no such difference in the magnitude of long-term potentiation between slices. Stimulation protocol 2 induced long-term depression only in slices from twoand 12-week-old rats. Comparison of the dynamic range of transmission plasticity in slices from two-and 36-week-old rats, calculated as the difference between the nearly saturated long-term potentiation and nearly saturated depotentiation, revealed a significantly smaller dynamic range in slices from 36-week-old rats in comparison with slices from two-week-old animals. The decrease in the dynamic range in slices from 36-week-old rats was due to a diminished capacity to depotentiate the nearly saturated long-term potentiation and not due to a decreased long-term potentiation expression in these slices. In contrast to long-term depression, in which the slope of the field excitatory postsynaptic potentials consistently and significantly decreased below the baseline level, the nearly saturated depotentiation did not decrease below the original, pre-long potentiation baseline level.The results demonstrate that increasing age reduces expression of long-term depression and the dynamic range of transmission plasticity.1998 IBRO. Published by Elsevier Science Ltd.

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Heterosynaptic depression: a postsynaptic correlate of long-term potentiation

Cited by 555 publications

References 8 publications

The adenosine kinase hypothesis of epileptogenesis

The adenosine kinase hypothesis of epileptogenesis

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

Increasing age reduces expression of long-term depression and dynamic range of transmission plasticity in CA1 field of the rat hippocampus

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