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Abstract Perisynaptic astroglia provide critical molecular and structural support to regulate synaptic transmission and plasticity in the nanodomain of the axon-spine interface. Three-dimensional reconstruction from serial section electron microscopy (3DEM) was used to investigate relationships between perisynaptic astroglia and dendritic spine synapses undergoing plasticity in the hippocampus of awake adult male rats. Delta-burst stimulation (DBS) of the medial perforant pathway induced long-term potentiation (LTP) in the middle molecular layer and concurrent long-term depression (cLTD) in the outer molecular layer of the dentate gyrus. The contralateral hippocampus received baseline stimulation as a within-animal control. Brains were obtained 30 minutes or 2 hours after DBS onset. An automated 3DEM pipeline was developed to enable unbiased quantification of astroglial coverage at the perimeter of the axon-spine interface. Under all conditions, >85% of synapses had perisynaptic astroglia processes within 120 nm of some portion of the perimeter. LTP broadened the distribution of spine sizes while reducing the presence and proximity of perisynaptic astroglia near the axon-spine interface of large spines. In contrast, cLTD transiently reduced the length of the axon-spine interface perimeter without substantially altering astroglial apposition. The postsynaptic density was discovered to be displaced from the center of the axon-spine interface, with this offset increasing during LTP and decreasing during cLTD. Astroglial access to the postsynaptic density was diminished during LTP and enhanced during cLTD, in parallel with changes in spine size. Thus, access of perisynaptic astroglia to synapses is dynamically modulated during LTP and cLTD alongside synaptic remodeling. Significance StatementPerisynaptic astroglia provide critical molecular and structural regulation of synaptic plasticity underlying learning and memory. The hippocampal dentate gyrus, a brain region crucial for learning and memory, was found to have perisynaptic astroglia at the axon-spine interface of >85% of excitatory synapses measured. Long-term potentiation triggered the retraction of perisynaptic astroglia processes selectively from large synapses. This retraction decreased access of perisynaptic astroglia to the postsynaptic density, which was discovered to be located off-center in the axon-spine interface. Concurrent long-term depression temporarily (< 2 h) decreased spine perimeter and thus increased access of synapses to perisynaptic astroglia. These findings provide new insights into how the structural dynamics of spines and synapses shape access to perisynaptic astroglia.
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This content will become publicly available on April 22, 2026
Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties. In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis. This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns.
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- Award ID(s):
- 2014862
- PAR ID:
- 10623811
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Publisher / Repository:
- PNAS
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 122
- Issue:
- 16
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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