Basal Synapses Research Articles

A structural dynamics model for how CPEB3 binding to SUMO2 can regulate translational control in dendritic spines.

A prion-like RNA-binding protein, CPEB3, can regulate local translation in dendritic spines. CPEB3 monomers repress translation, whereas CPEB3 aggregates activate translation of its target mRNAs. However, the CPEB3 aggregates, as long-lasting prions, may raise the problem of unregulated translational activation. Here, we propose a computational model of the complex structure between CPEB3 RNA-binding domain (CPEB3-RBD) and small ubiquitin-like modifier protein 2 (SUMO2). Free energy calculations suggest that the allosteric effect of CPEB3-RBD/SUMO2 interaction can amplify the RNA-binding affinity of CPEB3. Combining with previous experimental observations on the SUMOylation mode of CPEB3, this model suggests an equilibrium shift of mRNA from binding to deSUMOylated CPEB3 aggregates to binding to SUMOylated CPEB3 monomers in basal synapses. This work shows how a burst of local translation in synapses can be silenced following a stimulation pulse, and explores the CPEB3/SUMO2 interplay underlying the structural change of synapses and the formation of long-term memories.

Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses.

The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.

Pre-plaque Aß-Mediated Impairment of Synaptic Depotentiation in a Transgenic Rat Model of Alzheimer's Disease Amyloidosis.

How endogenously produced soluble amyloid ß-protein (Aß) affects synaptic plasticity in vulnerable circuits should provide insight into early Alzheimer’s disease pathophysiology. McGill-R-Thy1-APP transgenic rats, modeling Alzheimer’s disease amyloidosis, exhibit an age-dependent soluble Aß-mediated impairment of the induction of long-term potentiation (LTP) by 200 Hz conditioning stimulation at apical CA3-to-CA1 synapses. Here, we investigated if synaptic weakening at these synapses in the form of activity-dependent persistent reversal (depotentiation) of LTP is also altered in pre-plaque rats in vivo. In freely behaving transgenic rats strong, 400 Hz, conditioning stimulation induced stable LTP that was NMDA receptor- and voltage-gated Ca2+ channel-dependent. Surprisingly, the ability of novelty exploration to induce depotentiation of 400 Hz-induced LTP was impaired in an Aß-dependent manner in the freely behaving transgenic rats. Moreover, at apical synapses, low frequency conditioning stimulation (1 Hz) did not trigger depotentiation in anaesthetized transgenic rats, with an age-dependence similar to the LTP deficit. In contrast, at basal synapses neither LTP, induced by 100 or 200 Hz, nor novelty exploration-induced depotentiation was impaired in the freely behaving transgenic rats. These findings indicate that activity-dependent weakening, as well as strengthening, is impaired in a synapse- and age-dependent manner in this model of early Alzheimer’s disease amyloidosis.

Connectomics of synaptic microcircuits: lessons from the outer retina.

Photoreceptors form a sophisticated synaptic complex with bipolar and horizontal cells, transmitting the signals generated by the phototransduction cascade to downstream retinal circuitry. The cone photoreceptor synapse shows several characteristic anatomical connectivity motifs that shape signal transfer: typically, ON-cone bipolar cells receive photoreceptor input through invaginating synapses; OFF-cone bipolar cells form basal synapses with photoreceptors. Both ON- and OFF-cone bipolar cells are believed to sample from all cone photoreceptors within their dendritic span. Electron microscopy and immunolabelling studies have established the robustness of these motifs, but have been limited by trade-offs in sample size and spatial resolution, respectively, constraining precise quantitative investigation to a few individual cells. 3D-serial electron microscopy overcomes these limitations and has permitted complete sets of neurons to be reconstructed over a comparatively large section of retinal tissue. Although the published mouse dataset lacks labels for synaptic structures, the characteristic anatomical motifs at the photoreceptor synapse can be exploited to identify putative synaptic contacts, which has enabled the development of a quantitative description of outer retinal connectivity. This revealed unexpected exceptions to classical motifs, including substantial interaction between rod and cone pathways at the photoreceptor synapse, sparse photoreceptor sampling and atypical contacts. Here, we summarize what was learned from this study in a more general context: we consider both the implications and limitations of the study and identify promising avenues for future research.

Which molecules regulate synaptic brain asymmetries?

Which molecules regulate synaptic brain asymmetries?

Switching off LTP: mGlu and NMDA Receptor-Dependent Novelty Exploration-Induced Depotentiation in the Rat Hippocampus

Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

Differential distribution of glutamate receptors in the cochlear nuclei

Glutamate receptors are the major excitatory neurotransmitter receptors of the mammalian central nervous system, and include AMPA, kainate, delta, NMDA, and metabotropic types. In the cochlear nucleus (CN), the AMPA receptor subunits GluR2-4 are found in major kinds of neurons, while GluR1 subunit distribution is more restricted. GluR2 is low in the anteroventral CN, suggesting that many AMPA receptors here are calcium-permeable. Delta receptors are most prevalent in cartwheel cells in the dorsal CN. Of the NMDA receptors, NR1 is widespread while the NR2 subunits show more restricted distributions. Of the metabotropic glutamate receptors, mGluR1α is most prevalent in the dorsal CN, and mGluR2 is concentrated in Golgi cells and unipolar brush cells. AMPA receptors in endbulb synapses in the anteroventral CN are mainly GluR3+4 complexes: probably an adaptation for rapid auditory neurotransmission. Glutamate receptors are differentially distributed in synapses of fusiform cells of the dorsal CN; GluR4 and mGluR1α are present only at basal dendrite synapses (auditory nerve), while other glutamate receptors occupy both apical and basal synapses. Analysis of cytoplasmic distribution suggests that a selective targeting mechanism may restrict movement of GluR4 and mGluR1α to basal dendrites, although other targeting mechanisms may be present.

Synapses between cones and diffuse bipolar cells of a primate retina.

The photoreceptor synapses of three representative cells of the six types of diffuse bipolar cell of the rhesus macaque monkey's retina are described at 3.5-4.0 mm eccentricity. Bipolar cell DB3 was found to be postsynaptic to 11 cones at 155 basal synapses; about 70% of these were triad associated. Bipolar cell DB4 as postsynaptic to eight cones at 52 ribbon synapses; in addition it was found also to make an average of two or three basal (non-ribbon) synapses per cone (total 23). The DB5 bipolar cell type had 57 invaginating synapses with seven cones. It too had basal synapses, but only two with each of three cones. The diffuse invaginating bipolar cell described by Mariani (1981) is identified as a member of the DB5 category. Dendrites of cone bipolar cell types which have axons ending in the a-layer of the inner plexiform layer make only basal synapses with the cone pedicle. Those so far investigated are the flat midget bipolar cell and the DB2 and DB3 flat diffuse bipolar cells. All bipolar cells whose axons terminate in the b-layer of the inner plexiform layer are postsynaptic at the ribbon synapses of the cone pedicles. They now appear to fall into two groups. Those whose dendrites are exclusively postsynaptic at the ribbons; these are the blue cone and invaginating midget bipolar cells. And the diffuse bipolar cell DB4, that has both ribbon and basal synapses in a ratio of about 2.3:1. It is uncertain into which category cell DB5 should be placed; its basal synapses are so few the cell could be anomalous. It now seems that at least one primate bipolar cell type may be like those of other vertebrates in having, as defined ultrastructurally, two different kinds of synaptic connection with its cones. The results are discussed in the context of a brief review of the photoreceptor synapses of other mammalian bipolar cells.

Origins of the variations in long‐term potentiation between synapses in the basal versus apical dendrites of hippocampal neurons

Responses to theta pattern stimulation, and the long-term potentiation (LTP) they induce, were compared in the basal versus apical dendrites of neurons in field CA1 of hippocampus. A series of 10 theta bursts produced more than twice as much LTP in basal synapses as in their apical counterparts as measured with field EPSPs. This confirms earlier field potential studies showing that the maximum degree of potentiation (the LTP ceiling) is considerably greater in stratum oriens than stratum radiatum. Experiments with whole-cell clamp recording obtained similar results, indicating that synapses at different loci on the same neuron reach different LTP ceilings following prolonged theta burst stimulation. The basal synapses also required fewer theta bursts to reach their LTP ceiling than did the apical synapses. Tests with paired-pulse facilitation and an antagonist of the NMDA receptor gave no indication that the greater LTP in basal synapses was qualitatively different from the lesser effect obtained in apical contacts. Intracellular recording revealed significant differences between basal versus apical responses to single theta bursts and trains of bursts: the within-burst depolarization was greater and the between-burst hyperpolarization was smaller for the basal dendritic responses. These two variables have previously been proposed to influence the magnitude of LTP and the observed differences between basal versus apical synapses are in accord with this hypothesis. Together with recently described immunocytochemical results, the findings reported here suggest that variations in LTP across dendritic subfields of hippocampus reflect a differential distribution of a subclass of GABAergic interneurons.