CA3-CA1 Synapses In Hippocampus Research Articles

Intravascular Ketamine Increases Theta-Burst but Not High Frequency Tetanus Induced LTP at CA3-CA1 Synapses Within Three Hours and Devoid of an Increase in Spine Density.

In the past 20 years, ketamine has become a promising treatment for Major Depressive Disorder (MDD) due to its rapid and sustain antidepressant effects in patients. A single ketamine treatment causes improvement in depressive symptoms within hours and can last weeks, long after it is eliminated. Previous studies have demonstrated increased synaptic plasticity at CA3-CA1 synapses in hippocampus (HPC) 24 h post ketamine treatment suggesting increased activity-dependent hippocampal function may underlie the antidepressant effects of ketamine. If true, these changes should also occur within hours of treatment, a time when symptoms are first alleviated in patients. To determine if augmented synaptic plasticity is observed at an earlier time point, we measured theta-burst and high frequency tetanus induced long-term potentiation (LTP) at CA3-CA1 synapses 3 h following intravenous (IV) ketamine administration. Additionally, we measured basal hippocampal function and spine density to investigate whether connectivity was increased with ketamine treatment. We report that theta-burst but not high frequency tetanus induced LTP is significantly increased 3 h after in vivo ketamine with no changes in basal synaptic function or morphology. Our finding supports increased activity-dependent hippocampal function underlying the antidepressant effects of ketamine as it occurs at a time point that correlates with initial improvements of depressive symptoms in patients.

O‐GlcNAcylation Modulates Hippocampal Plasticity and Alters Hippocampal Dependent Learning and Memory

O‐GlcNAcylation is a dynamic posttranslational modification involving O‐linked addition of β‐N‐acetylglucosamine (GlcNAc) to serine/threonine residues on nucleocytoplasmic proteins. Hippocampal neurons express high levels of OGT and OGA, enzymes that add and remove O‐GlcNAc moieties. We investigated whether increasing O‐GlcNAcylation, with glucosamine or the OGA inhibitor Thiamet‐G, modulates synaptic transmission at CA3‐CA1 synapses in hippocampus, a brain region required for learning and memory. We find that increased O‐GlcNAcylation induces a novel long‐term depression (glucosamine: 85% ± 2.6% and Thiamet‐G: 81% ± 4.1% of baseline) and causes decrementing long‐term potentiation (control: 137 ± 4%, Thiamet‐G: 122 ± 6% of baseline). We also find that AMPA receptor GluA2, but not GluA1, subunits are O‐GlcNAcylated. We further demonstrate that increasing O‐GlcNAcylation in vivo interferes with novel object recognition while contextual fear conditioning is intact. These findings support the notion that an acute change in O‐GlcNAcylation of synaptic proteins is a novel fundamental mechanism capable of modulating synaptic efficacy and memory processing.

Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3–CA1 synapses

When circulating estrogen levels decline as a natural consequence of menopause and aging in women, there is an increased incidence of deficits in working memory. In many cases, these deficits are rescued by estrogen replacement therapy. These clinical data therefore highlight the importance of defining the biological pathways linking estrogen to the cellular substrates of learning and memory. It has been known for nearly two decades that estrogen enhances dendritic spine density on apical dendrites of CA1 pyramidal cells in hippocampus, a brain region required for learning. Interestingly, at synapses between CA3-CA1 pyramidal cells, estrogen has also been shown to enhance synaptic NMDA receptor current and the magnitude of long-term potentiation, a cellular correlate of learning and memory. Given that synapse density, NMDAR function, and long-term potentiation at CA3-CA1 synapses in hippocampus are associated with normal learning, it is likely that modulation of these parameters by estrogen facilitates the improvement in learning observed in rats, primates and humans following estrogen replacement. To facilitate the design of clinical strategies to potentially prevent or reverse the age-related decline in learning and memory during menopause, the relationship between the estrogen-induced morphological and functional changes in hippocampus must be defined and the role these changes play in facilitating learning must be elucidated. The aim of this report is to provide a summary of the proposed mechanisms by which this hormone increases synaptic function and in doing so, it briefly addresses potential mechanisms contributing to the estrogen-induced increase in synaptic morphology and plasticity, as well as important future directions.

Presynaptic calcium is increased during normal synaptic transmission and paired-pulse facilitation, but not in long-term potentiation in area CA1 of hippocampus

We examined the relationship between presynaptic calcium levels and postsynaptic potentials during normal synaptic transmission, paired-pulse facilitation (PPF), and long-term potentiation (LTP) in CA3-CA1 synapses of hippocampus. By selectively loading the presynaptic terminals with the calcium indicator fura-2, we simultaneously recorded a presynaptic calcium (Ca) transient and the corresponding field EPSP evoked by a single stimulus given to the Schaffer collateral-commissural pathway in guinea pig hippocampal slices. A volume average presynaptic Ca influx was obtained by taking the first time derivative of the Ca transient. Our data indicate that the synaptic transmission represented by the initial slope of the field EPSP is approximately proportional to the fourth power of the presynaptic Ca influx, the volume average Ca current. Our results in combination with similar findings at the squid giant synapse (Augustine et al., 1985b; Augustine and Charlton, 1986) suggest that the relationship between Ca influx and transmitter release is well conserved from the molluscan to the mammalian nervous system. A transient increase of the residual Ca level ([Ca]res) is generally thought to be the mechanism underlying PPF (Katz and Miledi, 1968; Charlton et al., 1982); however, the relationship between PPF and the presynaptic [Ca]res had not been examined before. Our results demonstrate that PPF is approximately linearly related to the [Ca]res. This finding further supports the residual Ca hypothesis for PPF. Accumulated evidence from other groups suggests that the presynaptic site contributes to the maintenance of LTP in CA3-CA1 synapses (Bekkers and Stevens, 1990; Malinow and Tsien, 1990); however, our data show that neither an increase of the Ca transient nor a sustained increase of the [Ca]res occurs in the presynaptic terminals during maintenance of LTP. This suggests that the presynaptic mechanism underlying LTP must be downstream to Ca influx.