Two Novel Forms of Spike Timing-Dependent Depression at Entorhinal Cortex-Hippocampal Synapses

Core Concepts

The entorhinal cortex conveys spatial, limbic and sensory information to the hippocampus, and the excitatory projections from the entorhinal cortex to the dentate gyrus play a role in memory encoding. This study discovered two novel forms of presynaptic spike timing-dependent long-term depression (t-LTD) at the lateral and medial perforant pathway synapses onto dentate gyrus granule cells, with distinct mechanistic requirements.

Abstract

The study investigated whether spike timing-dependent long-term depression (t-LTD) exists at the excitatory synaptic connections between the entorhinal cortex and the dentate gyrus in mice, and whether they have different action mechanisms.
The key findings are:

Two different forms of presynaptic t-LTD were identified at the lateral perforant pathway (LPP) and medial perforant pathway (MPP) synapses onto dentate gyrus granule cells.

The t-LTD at LPP-GC synapses does not require NMDAR, but the t-LTD at MPP-GC synapses requires ionotropic NMDARs containing GluN2A subunits.

The two forms of t-LTD require different group I metabotropic glutamate receptors (mGluRs), with LPP-GC synapses dependent on mGluR5 and MPP-GC t-LTD requiring mGluR1.

Both forms of t-LTD require postsynaptic calcium release from intracellular stores, endocannabinoid synthesis, CB1 receptor signaling, astrocyte activity, and glutamate, likely released by astrocytes.

The t-LTD at LPP-GC synapses, but not MPP-GC synapses, also requires postsynaptic calcineurin phosphatase activity.

These results demonstrate the existence of two novel forms of presynaptic t-LTD at entorhinal cortex-dentate gyrus synapses with distinct mechanistic requirements, which may have implications for information processing in the hippocampus.

Stats

"The induction of t-LTD at LPP-GC synapses was unaffected by exposure to nimodipine (10 µM) but it was prevented by treatment with thapsigargin (10 µM), either in the superfusion fluid or when loaded into the postsynaptic cell."
"The induction of t-LTD at MPP-GC synapses was unaffected in nimodipine-treated slices (10 µM) but prevented in slices treated with thapsigargin (10 µM), either in the superfusion fluid or when loaded into the postsynaptic cell."
"t-LTD induction was prevented at LPP-GC (110 ± 7 %, n = 8) but not MPP-GC synapses (72 ± 7 %, n = 6) when the calcineurin blocker FK506 (10 µM) was added to the superfusion fluid."

Quotes

"We discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses."
"Both these two forms of t-LTD require eCB synthesis and CB1R activation, and both require astrocytes and astrocyte signalling to promote gliotransmitter release, as well as glutamate that is probably released by astrocytes."

Key Insights Distilled From

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

by Coatl-Cuaya,... at www.biorxiv.org 03-29-2024

https://www.biorxiv.org/content/10.1101/2024.03.25.586546v1

Deeper Inquiries

How do the distinct mechanisms underlying t-LTD at LPP-GC and MPP-GC synapses contribute to the functional differences between these two pathways in information processing within the hippocampal circuit

The distinct mechanisms underlying t-LTD at LPP-GC and MPP-GC synapses play a crucial role in shaping the functional differences between these two pathways in information processing within the hippocampal circuit. The lateral perforant pathway (LPP) is associated with conveying more sensory-related information, while the medial perforant pathway (MPP) is involved in transmitting spatial and limbic signals. The differences in the mechanisms of t-LTD at these synapses contribute to the unique processing of information from these pathways.
At LPP-GC synapses, t-LTD does not require NMDAR activation, indicating a different molecular mechanism compared to MPP-GC synapses where t-LTD is NMDAR-dependent. This distinction suggests that the plasticity of these synapses is regulated differently, potentially influencing the encoding and processing of sensory information from the LPP and spatial information from the MPP. The requirement of specific mGluR subtypes further emphasizes the differential regulation of synaptic plasticity at these pathways, highlighting their specialized roles in information processing within the hippocampal circuit.
Overall, the unique mechanisms underlying t-LTD at LPP-GC and MPP-GC synapses contribute to the functional specialization of these pathways in processing distinct types of information, ultimately shaping the overall function of the hippocampal circuit in learning and memory.

What are the potential implications of the astrocyte-dependent nature of these t-LTD forms for understanding the role of glial cells in synaptic plasticity and memory formation

The astrocyte-dependent nature of t-LTD forms uncovered in this study sheds light on the critical role of glial cells in synaptic plasticity and memory formation. Astrocytes have long been recognized as active participants in synaptic transmission and plasticity, and their involvement in t-LTD at entorhinal cortex-dentate gyrus synapses further underscores their significance in modulating neuronal activity and information processing.
By demonstrating that astrocytes are required for the induction of t-LTD at both LPP-GC and MPP-GC synapses, this study highlights the dynamic interplay between neurons and glial cells in regulating synaptic plasticity. Astrocytes are known to release gliotransmitters, such as glutamate, ATP, and D-serine, which can modulate synaptic transmission and contribute to the plasticity of neuronal circuits. In the context of t-LTD, astrocytes likely play a crucial role in mediating the release of signaling molecules that influence presynaptic neurotransmitter release and synaptic efficacy.
Understanding the astrocyte-dependent mechanisms of t-LTD not only enhances our knowledge of the complex interactions within the brain's microenvironment but also opens up new avenues for exploring the therapeutic potential of targeting astrocytic signaling pathways in the treatment of neurological disorders associated with synaptic dysfunction and memory deficits.

Could the insights gained from this study on the differential regulation of synaptic plasticity at entorhinal cortex-dentate gyrus connections be leveraged to develop targeted interventions for neurological disorders like Alzheimer's disease and temporal lobe epilepsy, where these pathways are affected

The insights gained from the differential regulation of synaptic plasticity at entorhinal cortex-dentate gyrus connections offer promising implications for the development of targeted interventions for neurological disorders like Alzheimer's disease and temporal lobe epilepsy, where these pathways are affected.
In Alzheimer's disease, the dysfunction of entorhinal cortex-hippocampal synapses is a hallmark of the early stages of the disease, leading to memory impairment and cognitive decline. By understanding the specific mechanisms of t-LTD at LPP-GC and MPP-GC synapses, researchers can potentially develop targeted therapies that aim to modulate synaptic plasticity in these pathways to mitigate the synaptic deficits associated with Alzheimer's disease.
Similarly, in temporal lobe epilepsy, aberrant synaptic plasticity and hyperexcitability in the entorhinal cortex-hippocampal circuit contribute to seizure generation and propagation. Targeting the mechanisms underlying t-LTD at these synapses could offer novel therapeutic strategies to restore normal synaptic function and prevent the pathological changes that lead to epilepsy.
By leveraging the knowledge of the differential regulation of synaptic plasticity at these critical synapses, researchers and clinicians can explore innovative approaches to modulate synaptic transmission and memory processes in the context of neurological disorders, ultimately paving the way for more effective treatments and interventions.