skip to main content

Title: Developmental onset of enduring long-term potentiation in mouse hippocampus
Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L-LTP), lasting three or more hours, first occurs at postnatal day 12 (P12) in Long-Evans rat hippocampus. The goal of the current work was to determine the developmental onset of L-LTP in mouse hippocampus as a basis for comparing potential effects of key genetic manipulations known to affect dendritic spine structure. Four mouse strains were tested. Both C57BL/6 and Fmr1-/y mice on the C57BL/6 background began to show reliable L-LTP at P35. In contrast, both 129SVE wild type and Hevin- /- (Sparcl1-/-) on the 129SVE background first showed reliable L-LTP at P28. All strains showed a gradual progression between P10 to P28 in success rate for short-term potentiation (STP), which lasts one hour or less. At P10 in rats, two episodes of TBS result in L-LTP when he time between episodes was > 90 minutes. In mice, multiple bouts of TBS at various inter-bout intervals did not advance the onset age of L-LTP. Prior work in rats showed the onset of L-LTP at P12 coincided with the first formation of dendritic spines. In contrast, hippocampal dendritic spines are present more » by P24 in C57BL/6 mice, well before the onset age for L-LTP. These speciesdependent findings suggest that dendritic spines may be necessary but not sufficient for L-LTP. « less
Authors:
Award ID(s):
1707356
Publication Date:
NSF-PAR ID:
10171014
Journal Name:
PloS one
ISSN:
1932-6203
Sponsoring Org:
National Science Foundation
More Like this
  1. AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits and play important roles in synaptic transmission and plasticity. Here, we have investigated the development of AMPAR-mediated synaptic transmission in the hippocampus of the Fmr1 knock-out (KO) mouse, a widely used model of Fragile X syndrome (FXS). FXS is the leading monogenic cause of intellectual disability and autism spectrum disorders (ASD) and it is considered a neurodevelopmental disorder. For that reason, we investigated synaptic properties and dendritic development in animals from an early stage when synapses are starting to form up to adulthood. We found that hippocampal CA1 pyramidal neurons in the Fmr1-KO mouse exhibit a higher AMPAR-NMDAR ratio early in development but reverses to normal values after P13. This increase was accompanied by a larger presence of the GluA2-subunit in synaptic AMPARs that will lead to altered Ca 2+ permeability of AMPARs that could have a profound impact upon neural circuits, learning, and diseases. Following this, we found that young KO animals lack Long-term potentiation (LTP), a well-understood model of synaptic plasticity necessary for proper development of circuits, and exhibit an increased frequency of spontaneous miniature excitatory postsynaptic currents, a measure of synaptic density.more »Furthermore, post hoc morphological analysis of recorded neurons revealed altered dendritic branching in the KO group. Interestingly, all these anomalies are transitory and revert to normal values in older animals. Our data suggest that loss of FMRP during early development leads to temporary upregulation of the GluA2 subunit and this impacts synaptic plasticity and altering morphological dendritic branching.« less
  2. Long-term potentiation (LTP), an increase in synaptic efficacy following high-frequencystimulation, is widely considered a mechanism of learning. LTP involves local remodeling ofdendritic spines and synapses. Smooth endoplasmic reticulum (SER) and endosomal compartmentscould provide local stores of membrane and proteins, bypassing the distant Golgi apparatus. Totest this hypothesis, effects of LTP were compared to control stimulation in rat hippocampal areaCA1 at postnatal day 15 (P15). By two hours, small spines lacking SER increased after LTP, whereaslarge spines did not change in frequency, size, or SER content. Total SER volume decreased afterLTP consistent with transfer of membrane to the added spines. Shaft SER remained more abundantin spiny than aspiny dendritic regions, apparently supporting the added spines. Recyclingendosomes were elevated specifically in small spines after LTP. These findings suggest localsecretory trafficking contributes to LTP-induced synaptogenesis and primes the new spines forfuture plasticity.
  3. Berry, Hugues (Ed.)
    Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity inmore »the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.« less
  4. Hugues Berry (Ed.)
    Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity inmore »the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.« less
  5. Hugues Berry (Ed.)
    Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity inmore »the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.« less