Structural LTP: from synaptogenesis to regulated synapse enlargement and clustering
Introduction
Analysis of LTP provides a powerful window into cellular mechanisms of learning. Hence, LTP is mostly studied in the hippocampus, a brain region required to form memories. The importance of prior activation history and specific induction paradigms are increasingly emphasized to understand mechanisms of LTP [1, 2, 3]. Dendritic spines are tiny protrusions that stud the surface of dendrites and host most of the excitatory synapses throughout the brain. The importance of context arises even when single spine synapses are potentiated by glutamate uncaging [3]. Most experiments image changes in spine structure as a proxy for synapse growth, and usually end within an hour after onset of potentiation. Such experiments have revealed exquisite detail about molecular and cellular mechanisms controlling spine structural plasticity during the early phase of LTP. Here we consider more enduring structural LTP in the context of developmental stage and availability of local resources.
Section snippets
LTP enhances synaptogenesis at P15 but stalls spine outgrowth in adults
To investigate enduring LTP, hippocampal slices are prepared, allowed to rest for 3−4 hours, and then test pulses are delivered at a frequency of one per 2 min for 30−40 min to establish baseline response. Then LTP is induced with a pattern of theta-burst stimulation (TBS) that fully saturates LTP [4,5]. The number and frequency of test pulses is matched in control and LTP conditions for varying times post-TBS. Three-dimensional reconstruction from serial section electron microscopy (3DEM)
Resource dependent synapse enlargement and synaptogenesis
Multiple subcellular resources contribute locally to structural LTP. Smooth endoplasmic reticulum (SER) is a continuous internal membrane system that extends from the cell body into dendrites and into some spines. The SER regulates calcium and the synthesis and trafficking of lipids and proteins [8]. In locations where the SER elaborates, ER exit sites abound and can deliver resources of membrane and proteins to synapses [9••]. The spine apparatus is a structure elaborated from SER into
Maturation of homeostasis and spine clustering
Recent experiments using optogenetics, live imaging, and computational models suggest that clusters of spines cooperate to enhance the efficacy of particular inputs during plasticity and learning [18•,19••,20,21•,22, 23, 24]. The redistribution of subcellular resources could be critical in determining where such spine clustering hotspots arise. During LTP, do the enlarging synapses on SA-containing spines sequester resources and prevent neighboring spine outgrowth, or do they share with
Silent formation and enlargement of synapses
Curiously, synaptogenesis and synapse enlargement appear to be silent at P15 and adult hippocampus. Enhanced synaptogenesis with LTP (P15) or recovery of spines during control stimulation in adults are both silent. This conclusion is obvious from looking at the time course of spine formation during control stimulation or LTP relative to the physiological response across time during LTP experiments (Figure 4a). In adults, if the spines that recovered in response to control stimulation were
Presynaptic axons track postsynaptic changes
Presynaptic plasticity is also developmentally regulated by LTP [28, 29, 30]. At P15, more presynaptic boutons form to accommodate the LTP-induced synaptogenesis. In adults, fewer presynaptic boutons accompany stalled spine outgrowth after LTP. At both ages, a drop in presynaptic vesicles remains for at least 2 hours after TBS-induction of LTP, especially in boutons with mitochondria [29]. This drop could reflect the elevated recycling of presynaptic vesicles detected 30 min post induction of LTP
Other considerations
Several other factors may contribute to the maturation of homeostasis and dendritic spine clustering. We focused here on the extent to which dendritic shaft SER and the associated ER exit sites may serve to define regions of dendritic spine clustering. The post-LTP spread of numerous other molecules may be restricted to individual spines or short regions of the dendritic shaft [2,33,34]. Differential expression of calcium-permeable AMPA receptors could influence the range over which a calcium
Conclusion
Despite dramatic structural plasticity, and daily turnover of synaptic proteins, memories stored in synapses show remarkable tenacity. Synapse stabilization appears to require reactivation, especially during sleep [41,42]. Failure of synapses to form, grow, or remodel is likely responsible for many developmental and age-related disorders. [43]. It remains unclear whether dendritic spine loss is a cause or consequence. Observing that dendrites retain immature varicosities and filopodia in
Conflict of interest statement
Nothing declared.
Funding
R01MH095980 NSF NeuroNex Neurotechnology Hub #1707356.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as
• of special interest
•• of outstanding interest
Acknowledgement
I thank Patrick Parker for editorial comments and Masa Kuwajima for help with Figure 3.
References (43)
Dendritic spines: morphological building blocks of memory
Neurobiol Learn Mem
(2017)- et al.
Age-dependence in the homeostatic upregulation of hippocampal dendritic spine number during blocked synaptic transmission
Neuropharmacology
(2004) ER proteostasis control of neuronal physiology and synaptic function
Trends Neurosci
(2018)Polyribosomes are increased in spines of CA1 dendrites 2 h after the induction of LTP in mature rat hippocampal slices
Hippocampus
(2007)Presynaptic ultrastructure changes in response to LTP stimulation in stratum radiatum of hippocampal CA1 neuropil
Soc Neurosci
(2018)- et al.
Self-organized reactivation maintains and reinforces memories despite synaptic turnover
eLife
(2019) - et al.
Primed to sleep: the dynamics of synaptic plasticity across brain states
Front Syst Neurosci
(2019) - et al.
Plasticity of spine structure: local signaling, translation and cytoskeletal reorganization
Front Synaptic Neurosci
(2018) - et al.
Single synapse LTP: a matter of context?
Front Cell Neurosci
(2019) - et al.
Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP
Hippocampus
(2011)
LTP enhances synaptogenesis in the developing hippocampus
Hippocampus
Structural plasticity of dendritic secretory compartments during LTP-induced synaptogenesis
eLife
Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines
eLife
Architecture and dynamics of the neuronal secretory network
Annu Rev Cell Dev Biol
Shifting patterns of polyribosome accumulation at synapses over the course of hippocampal long-term potentiation
Hippocampus
Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation
Mol Brain
Local resources of polyribosomes and SER promote synapse enlargement and spine clustering after long-term potentiation in adult rat hippocampus
Sci Rep
Understanding the role of synaptopodin and the spine apparatus in Hebbian synaptic plasticity - new perspectives and the need for computational modeling
Neurobiol Learn Mem
Monosomes actively translate synaptic mRNAs in neuronal processes
Science
Myosin V regulates synaptopodin clustering and localization in the dendrites of hippocampal neurons
J Cell Sci
Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory
Nat Commun
Cited by (43)
Ultrasound modulates neuronal potassium currents via ionotropic glutamate receptors
2023, Brain StimulationComputational methods for ultrastructural analysis of synaptic complexes
2022, Current Opinion in NeurobiologyCitation Excerpt :In image segmentation, all pixels that represent a structure of interest are labeled, thus allowing a full 3D visualization. 3D segmentations of plasma membrane and cellular organelles of hippocampal tissue provided beautiful images of dendritic spines and synaptic contacts, and established strong links between spine shape, smooth endoplasmic reticulum organization and distribution of polyribosomes, and synaptic plasticity (Figure 1a, b) [34,4]. The images were provided by serial sectioning and TEM of chemically-fixed neuronal tissue (Box 1).
Role of the endoplasmic reticulum in synaptic transmission
2022, Current Opinion in NeurobiologyCitation Excerpt :The levels of electrical activity in neurons can shape not only the morphology and composition of the dendritic PM but also the dynamics of internal organelles. In mammalian central synapses, only a fraction of dendritic spines contain ER at any given time point (15%–50% [3,14]) this dendritic ER however is highly dynamic and over time it will transiently enter and explore most of the spines [15]. The mobility of the ER is positively regulated by neuronal activity and vice versa, manipulating the mobility of the ER can strengthen synapses influencing their capacity to undergo long-term potentiation (LTP) and depression (LTD) in the rodent hippocampus [15].
Dendritic and behavioral changes in rats neonatally treated with homocysteine; A proposal as an animal model to study the attention deficit hyperactivity disorder
2022, Journal of Chemical NeuroanatomyCitation Excerpt :It is interesting to highlight that we found a decrease in the number of mushroom spines in all the areas studied (PFC-3, DG, CA1 and NAcc) in adult rats treated neonatally with homocysteine. These mushroom spines are essential for having stable and functional synapsis (Harris, 2020). Instead, prepuberal rats only presented changes in this kind of dendritic spine in CA1 and NAcc.