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Direct cortical inputs erase long-term potentiation at Schaffer collateral synapses.

ABSTRACT: Long-term potentiation (LTP), a synaptic mechanism thought to underlie memory formation, has been studied extensively at hippocampal Schaffer collateral (SC) synapses. The SC pathway transmits information to area CA1 that originates in entorhinal cortex and is processed by the dentate gyrus and area CA3. CA1 also receives direct excitatory input from entorhinal cortex via the perforant path (PP), but the role of this cortical input is less certain. Here, we report that low-frequency stimulation of PP inputs to CA1 has no lasting effect on basal SC transmission, but effectively depotentiates SC synapses that have undergone LTP in a manner that can be reversed by subsequent high-frequency stimulation of SC inputs. This depotentiation does not require NMDA receptors, group I metabotropic glutamate receptors, or L-type calcium channels, but involves adenosine acting at A(1) receptors. Given the limited storage capacity of the hippocampus, these observations provide a mechanism by which input from cortex can help to reset synaptic transmission in the hippocampus and facilitate additional information processing.

SUBMITTER: Izumi Y

PROVIDER: S-EPMC2610347 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Direct cortical inputs erase long-term potentiation at Schaffer collateral synapses.

Izumi Yukitoshi Y Zorumski Charles F CF

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080901 38

Long-term potentiation (LTP), a synaptic mechanism thought to underlie memory formation, has been studied extensively at hippocampal Schaffer collateral (SC) synapses. The SC pathway transmits information to area CA1 that originates in entorhinal cortex and is processed by the dentate gyrus and area CA3. CA1 also receives direct excitatory input from entorhinal cortex via the perforant path (PP), but the role of this cortical input is less certain. Here, we report that low-frequency stimulation ...[more]

PMID: 18799687

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Project description:CA1 pyramidal neurons receive two distinct excitatory inputs that are each capable of influencing hippocampal output and learning and memory. The Schaffer collateral (SC) input from CA3 axons onto the more proximal dendrites of CA1 is part of the trisynaptic circuit, which originates in Layer II of the entorhinal cortex (EC). The temporoammonic (TA) pathway to CA1 provides input directly from Layer III of the EC onto the most distal dendrites of CA1 pyramidal cells, and is involved in spatial memory and memory consolidation. We have previously described a developmental decrease in short-term facilitation from juvenile (P13-18) to young adult (P28-42) rats at SC synapses that is due to feedback inhibition via synaptically activated mGluR1 on CA1 interneurons. It is not known how short-term changes in synaptic strength are regulated at TA synapses, nor is it known how short-term plasticity is balanced at SC and TA inputs during development. Here we describe a novel developmental increase in short-term facilitation at TA synapses, which is the opposite of the decrease in facilitation occurring at SC synapses. Although short-term facilitation is much lower at TA synapses when compared with SC synapses in juveniles, short-term plasticity at SC and TA synapses converges at similar levels of paired-pulse facilitation in the young adult rat. However, in young adults CA3-CA1 synapses still exhibit more facilitation than TA-CA1 synapses during physiologically-relevant activity, suggesting that the two pathways are each poised to uniquely modulate CA1 output in an activity-dependent manner. Finally, we show that there is a developmental decrease in the initial release probability at TA synapses that underlies their developmental decrease in facilitation, but no developmental change in release probability at SC synapses. This represents a fundamental difference in the presynaptic function of the two major inputs to CA1, which could alter the flow of information in hippocampus during development.

Project description:Long-term potentiation (LTP) is an activity-dependent and persistent increase in synaptic transmission. Currently available techniques to measure LTP are time-intensive and require highly specialized expertise and equipment, and thus are not well suited for screening of multiple candidate treatments, even in animal models. To expand and facilitate the analysis of LTP, here we use a flow cytometry-based method to track chemically induced LTP by detecting surface AMPA receptors in isolated synaptosomes: fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). First, we demonstrate that FASS-LTP is simple, sensitive, and models electrically induced LTP recorded in intact circuitries. Second, we conducted FASS-LTP analysis in two well-characterized Alzheimer's disease (AD) mouse models (3xTg and Tg2576) and, importantly, in cryopreserved human AD brain samples. By profiling hundreds of synaptosomes, our data provide the first direct evidence to support the idea that synapses from AD brain are intrinsically defective in LTP. Third, we used FASS-LTP for drug evaluation in human synaptosomes. Testing a panel of modulators of cAMP and cGMP signaling pathways, FASS-LTP identified vardenafil and Bay-73-6691 (phosphodiesterase-5 and -9 inhibitors, respectively) as potent enhancers of LTP in synaptosomes from AD cases. These results indicate that our approach could provide the basis for protocols to study LTP in both healthy and diseased human brains, a previously unattainable goal. SIGNIFICANCE STATEMENT:Learning and memory depend on the ability of synapses to strengthen in response to activity. Long-term potentiation (LTP) is a rapid and persistent increase in synaptic transmission that is thought to be affected in Alzheimer's disease (AD). However, direct evidence of LTP deficits in human AD brain has been elusive, primarily due to methodological limitations. Here, we analyze LTP in isolated synapses from AD brain using a novel approach that allows testing LTP in cryopreserved brain. Our analysis of hundreds of synapses supports the idea that AD-diseased synapses are intrinsically defective in LTP. Further, we identified pharmacological agents that rescue LTP in AD, thus opening up a new avenue for drug screening and evaluation of strategies for alleviating memory impairments.

Dataset Information

Direct cortical inputs erase long-term potentiation at Schaffer collateral synapses.

Publications

Direct cortical inputs erase long-term potentiation at Schaffer collateral synapses.

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