GABAB-receptor modulation of short-term synaptic depression at an excitatory input to murine hippocampal CA3 pyramidal neurons

Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.

Download Full-text

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

10.1101/846816 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nuno Apóstolo ◽

Samuel N. Smukowski ◽

Jeroen Vanderlinden ◽

Giuseppe Condomitti ◽

Vasily Rybakin ◽

...

Keyword(s):

Cell Surface ◽

Pyramidal Neurons ◽

Mossy Fiber ◽

Surface Protein ◽

Guidance Cue ◽

Hippocampal Ca3 ◽

Cell Surface Interactions ◽

Ca3 Pyramidal Neurons ◽

Ca3 Neurons ◽

Multiple Ligand

SummarySynaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.

Download Full-text

Ontogenesis of Presynaptic GABAB Receptor-Mediated Inhibition in the CA3 Region of the Rat Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.1998.79.3.1341 ◽

1998 ◽

Vol 79 (3) ◽

pp. 1341-1348 ◽

Cited By ~ 23

Author(s):

Olivier Caillard ◽

Heather A. McLean ◽

Yehezkel Ben-Ari ◽

Jean-Luc Gaïarsa

Keyword(s):

Pyramidal Neurons ◽

Gabab Receptor ◽

Hippocampal Slices ◽

Reversal Potential ◽

Rat Hippocampus ◽

Dependent Manner ◽

Paired Pulse ◽

Ca3 Pyramidal Neurons ◽

Paired Pulse Depression ◽

Ca3 Region

Caillard, Olivier, Heather A. McLean, Yehezkel Ben-Ari, and Jean-Luc Gaı̈arsa. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus. J. Neurophysiol. 79: 1341–1348, 1998. γ-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5–7 day old) and adult (27–34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μM) and d(−)2-amino-5-phosphovaleric acid (d-AP5, 50 μM) with 2(triethylamino)- N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blockedb y P - 3 - a m i n o p r o p y l - P - d i e t h o x y m e t h y l p h o s p h o r i c a c i d(CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 μM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites.

Download Full-text