Synaptic plasticity in the hippocampal slice: functional consequences

doi:10.1016/0165-0270(94)00188-M

Journal of Neuroscience Methods

Volume 59, Issue 1, June 1995, Pages 11-17

https://doi.org/10.1016/0165-0270(94)00188-M Get rights and content

Abstract

There are 3 known forms of synaptic plasticity at CNS synapses: long-term potentiation (LTP) mediated by NMDA receptor activation, LTP mediated by voltage-dependent calcium channel (VDCC) activation, and long-term depression (LTD) mediated by the NMDA receptor. All 3 forms of synaptic plasticity can be observed in hippocampal CA1 cells, all are induced by afferent activation, all involve Ca²⁺ influx, and all activate Ca²⁺-dependent mechanisms. We consider the functional consequences of the presence of 3, sometime opposing, forms of synaptic plasticity at the same synapse. We suggest that the 2 forms of LTP have different consequences for the synapse. We postulate that the co-existence of potentiating and depressing capabilities influences the network processing capabilities of neural networks.

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For example, induction of LTP via conventional methods requires activation of N-methyl-d-aspartate receptors (NMDARs). In contrast, induction of LTP with higher frequency stimulation (200–250 Hz) or in the presence of elevated extracellular calcium (Izumi and Zorumski, 1998) involves activation of voltage-dependent calcium channels (VDCCs) (Teyler et al., 1995). Since we were able to induce LTP with conventional methods in EE rats, we hypothesized that the LTP enhanced by EE was NMDAR-dependent.
Age-associated changes in cognition are mirrored by impairments in cellular models of memory and learning, such as long-term potentiation (LTP) and long-term depression (LTD). In young rodents, environmental enrichment (EE) can enhance memory, alter LTP and LTD, as well as reverse cognitive deficits induced by aging. Whether short-term EE can benefit cognition and synaptic plasticity in aged rodents is unclear. Here, we tested if short-term EE could overcome age-associated impairments in induction of LTP and LTD. LTP and LTD could not be induced in the CA1 region of hippocampal slices in control, aged rats using standard stimuli that are highly effective in young rats. However, exposure of aged littermates to EE for three weeks enabled successful induction of LTP and LTD. EE-facilitated LTP was dependent upon N-methyl-d-aspartate receptors (NMDARs). These alterations in synaptic plasticity occurred with elevated levels of phosphorylated cAMP response element-binding protein and vascular endothelial growth factor, but in the absence of changes in several other synaptic and cellular markers. Importantly, our study suggests that even a relatively short period of EE is sufficient to alter synaptic plasticity and molecular markers linked to cognitive function in aged animals.
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Control experiments with induction of LTP and previous application of nifedipine alone (without GABA-blockade) did not influence the maintenance of this control-LTP (percent potentiation measured as the field-e.p.s.p. seven hours after LTP induction: controls −168.7±16.3, series with nifedipine −165.2±17.5). These results indicate that conventional L-LTP induced by our stimulation protocol (3 bursts of 100 impulses, 100 Hz) did not require the activation of L-type VDCC, as reported by others (Malenka, 1991; Huber et al., 1995; Teyler et al., 1995; Hanse and Gustafsson, 1995). As mentioned above, the role of VDCC for the late enhancement of excitability after continuous GABA-receptor inhibition could not be investigated after tetanization.
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The human DLG3 gene encodes the synapse-associated protein 102 (SAP102), which is concentrated in the postsynaptic densities of excitatory synapses and involved in receptor-mediated synaptic transmission via binding to the NR2B subunit of the NMDA receptor. In this study, we investigated the expression and cellular distribution of the DLG3/SAP102 protein in human epileptic cortex. Tissue microarrays of a large number of specimens from patients operated for medically intractable epilepsy were used for immunohistochemical screening with anti-DLG3 antibody. The cellular distribution of the protein was further investigated in samples of malformations of cortical development, and the amount of DLG3 protein in the total homogenate and in the postsynaptic membrane fraction of these samples was quantified by Western blot. We found a strictly neuronal expression of DLG3/SAP102 in epileptogenic cortex as well as in non-epileptic human cortex used for control. In focal cortical dysplasia and tuberous sclerosis complex, the protein was expressed in most neurons including dysplastic neurons, but not in giant cells. Increased expression of DLG3 protein was observed in the postsynaptic membrane fraction of patients with focal cortical dysplasia. Double-labeling experiments confirmed the exclusive neuronal character of the DLG3 expressing cells and the co-localization of the DLG3 protein with the NR2B subunit. Our results suggest a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development.
17β-estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3
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We sought to determine the impact of 17β-estradiol throughout the hippocampal trisynaptic pathway and to investigate the afferent fiber systems within CA1 and CA3 in detail. To achieve this objective, we utilized multielectrode arrays to simultaneously record the field excitatory postsynaptic potentials from the CA1, dentate gyrus, and CA3 of rat hippocampal slices in the presence or absence of 100 pM 17β-estradiol. We confirmed our earlier findings in CA1, where 17β-estradiol significantly increased field excitatory postsynaptic potentials amplitude (20%±3%) and slope (22%±7%). 17β-Estradiol significantly potentiated the field excitatory postsynaptic potentials in dentate gyrus, amplitude (15%±4%) and slope (17%±5), and in CA3, amplitude (15%±4%) and slope (19%±5%). Using a high-density multielectrode array, we sought to determine the source of potentiation in CA1 and CA3 by determining the impact of 17β-estradiol on the apical afferents and the basal afferents within CA1 and on the mossy fibers and the associational/commissural fibers within CA3. In CA1, 17β-estradiol induced a modest increase in the amplitude (7%±2%) and slope (9%±3%) following apical stimulation with similar magnitude of increase following basal stimulation amplitude (10%±2%) and slope (12%±3%). In CA3, 17β-estradiol augmented the mossy fiber amplitude (15%±3%) and slope (18%±6%) and the associational/commissural fiber amplitude (31%±13%) and slope (40%±15%). These results indicate that 17β-estradiol potentiated synaptic transmission in each subfield of the hippocampal slice, with the greatest magnitude of potentiation at the associational/commissural fibers in CA3. 17β-Estradiol regulation of CA3 responses provides a novel site of 17β-estradiol action that corresponds to the density of estrogen receptors within the hippocampus. The implications of 17β-estradiol potentiation of the field potential in each of the hippocampal subfields and in particular CA3 associational/commissural fibers for memory function and clinical assessment are discussed.
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Citation Excerpt :
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Research paperSynaptic plasticity in the hippocampal slice: functional consequences

Abstract

The trk family of neurotrophin receptors

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

Co-activation of metabotropic glutamate and N-methyl-d-aspartate receptors is involved in mechanisms of long-term potentiation maintenance in rat hippocampal CA1 neurons

Neuroscience

Developmental approaches to the memory process

Enhanced neurotrophin receptor expression following long-term potentiation

Soc. Neurosci. Abst.

Dendritic localization of LTP and LTD

Soc. Neurosci. Abst.

Neurotrophin receptors

Prog. Neurobiol.

Alpha2-Macroglobulin is a binding protein for basic fibroblast growth factor

J. Biol. Chem.

Brain-derived neurotrophic factor after long-term potentiation

Neurosci. Lett.

Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-d-aspartate receptor blockade

Long-term potentiation in the hippocampal slice: evidence for stimulated secretion of newly synthesized proteins

Science

Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain

Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment

Neurosci. Lett.

Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons

Science

Limbic seizures increase neuronal production of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis

Neuron

Two components of LTP induced by different patterns of afferent activation

Nature

Different mechanisms may be required for maintenance of NMDA receptor dependent and independent forms of long-term potentiation

Synapse

Requirement for BDNF in activity-dependent survival of cortical neurons

Science

Alpha-2-Macroglobulin: a modulator for growth factors?

Am. J. Respir. Cell Mol. Biol.

Research paper
Synaptic plasticity in the hippocampal slice: functional consequences

Alpha₂-Macroglobulin is a binding protein for basic fibroblast growth factor