Reduced Perisomatic Inhibition, Increased Excitatory Transmission, and Impaired Long-Term Potentiation in Mice Deficient for the Extracellular Matrix Glycoprotein Tenascin-R

Saghatelyan, Armen; Dityatev, Alexander; Schmidt, Sandra; Schuster, T; Bartsch, Udo; Schachner, Melitta

doi:10.1006/mcne.2000.0922

Cited by 177 publications

(152 citation statements)

References 47 publications

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“…Bcan interacts with its C-type lectin domain with the ECM glycoprotein Tnr (Aspberg et al, 1997). LTP is impaired in mice that lack Bcan or Tnr, implicating a role of perineuronal nets in synaptic plasticity mechanisms (Saghatelyan et al, 2001;Brakebusch et al, 2002). Link proteins, such as Hapln1, are thought to have an important role in formation and stability of perineuronal nets (Carulli et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

Oever

Lubbers

Goriounova

et al. 2010

Neuropsychopharmacol

113

106

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Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administrationinduced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.

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Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

Oever

Lubbers

Goriounova

et al. 2010

Neuropsychopharmacol

113

106

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“…Previous studies revealed a reduction in TBS-induced LTP in the CA1 region of TNRϪ/Ϫ mice (Bukalo et al, 2001;Saghatelyan et al, 2001). To investigate whether reduced LTP in TNRϪ/Ϫ mice is caused by a shift in the threshold for induction of LTP, we now induced LTP in whole-cell voltage-clamp configuration, because this provides a tighter control of postsynaptic depolarization during induction of LTP than TBS combined with fEPSP recordings.…”

Section: Increased Threshold For Induction Of Ltp By Pairing In Tnr-dmentioning

confidence: 99%

“…Because impairment of TBS-induced LTP in TNRϪ/Ϫ mice is accompanied by elevated excitatory transmission and reduced perisomatic inhibition of CA1 pyramidal cells (Saghatelyan et al, 2001;Nikonenko et al, 2003), we tested whether experimental manipulations that would compensate for either of these abnormalities would lead to a recovery of LTP in mutant mice. To evaluate the significance of elevated excitatory transmission in CA3-CA1 synapses for induction of LTP, we attempted to induce LTP in TNRϪ/Ϫ mice after reduction of excitatory transmission via induction of LTD. Two trains of lowfrequency stimulation resulted in ϳ25% reduction of fEPSPs in both genotypes (Fig.…”

Section: Rescue Of Ltp In Tnr-deficient Mice By Agonists Of Gaba a Rementioning

confidence: 99%

“…In a previous study, we observed that the HNK-1 carbohydrate (human natural killer cell glycan, i.e., 3-sulfoglucuronyl beta1-3 galactoside) carried by TNR in the CA1 region of the hippocampus is involved in regulation of perisomatic, but not dendritic inhibition of pyramidal cells via reduction of evoked GABA release (Saghatelyan et al, 2000). Reduction in perisomatic inhibition in TNR-deficient mice (TNRϪ/Ϫ) coincided with reduced theta-burst stimulation (TBS)-induced long-term potentiation (LTP) and increased basal excitatory synaptic transmission in CA1 (Bukalo et al, 2001;Saghatelyan et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal Metaplasticity Induced by Deficiency in the Extracellular Matrix Glycoprotein Tenascin-R

Bukalo¹,

Schachner²,

Dityatev³

2007

J. Neurosci.

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Predisposition of synapses to undergo plastic changes can be dynamically adjusted according to the history of synaptic activity (i.e., synapses are metaplastic). In search of a molecular mechanism underlying metaplasticity, we investigated mice deficient in the glycoprotein tenascin-R (TNR), based on the observations that this mutant exhibits elevated basal excitatory synaptic transmission and reduced perisomatic GABAergic inhibition. TNR is a major extracellular matrix glycoprotein of the CNS and carries the HNK-1 carbohydrate (human natural killer cell glycan), which has been identified as the functional epitope mediating regulation of GABAergic transmission via GABA B receptors. Here, we used patch-clamp recordings in hippocampal slices to determine the critical levels of postsynaptic neuron depolarization necessary for induction of long-term potentiation (LTP) at CA3-CA1 synapses and found that deficiency in TNR leads to a metaplastic increase in the threshold for induction of LTP. Reconstitution of slices from TNR-deficient mice with an HNK-1 glycomimetic or pharmacological treatment with either a GABA A receptor agonist, a GABA B receptor antagonist, an L-type voltagedependent Ca 2ϩ channel blocker, or an inhibitor of protein serine/threonine phosphatases restored LTP to the levels seen in wild-type mice. We propose that a chain of events initiated by reduced GABAergic transmission and proceeding via Ca 2ϩ entry into cells and elevated activity of phosphatases mediates homeostatic adjustment of hippocampal plasticity in the absence of TNR. These data uncover a novel mechanism by which an extracellular matrix molecule and its associated carbohydrate provide conditions beneficial for induction of LTP in the CA1 region of the hippocampus.

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“…Several molecules (NCAM, tenascin-C, tenascin-R, F3/contactin, and PTN) interacting with the extracellular domain of Ptprz are shown to be implicated in synaptic plasticity in the hippocampus (Muller et al, 1996;Amet et al, 2001;Saghatelyan et al, 2001;Evers et al, 2002;Murai et al, 2002;Pavlov et al, 2002). In addition, Ptprz interacts intracellularly with the postsynaptic density-95 (PSD-95)/synapse-associated protein-90 family proteins (Kawachi et al, 1999), which are the synaptic scaffolding proteins involved in synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Age-Dependent Enhancement of Hippocampal Long-Term Potentiation and Impairment of Spatial Learning through the Rho-Associated Kinase Pathway in Protein Tyrosine Phosphatase Receptor Type Z-Deficient Mice

Niisato

Fujikawa²,

Komai³

et al. 2005

J. Neurosci.

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Although protein tyrosine phosphatases (PTPs) are expressed abundantly in the brain, their roles in synaptic plasticity have not been well elucidated. In this study, we have examined the physiological functions of Ptprz, which is a receptor-type PTP expressed predominantly in the brain as a chondroitin sulfate proteoglycan. We have examined phenotypes of mutant mice deficient in Ptprz using electrophysiological, pharmacological, and behavioral approaches. Mutant mice exhibit enhanced long-term potentiation (LTP) in the CA1 region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (Ͻ10 weeks old) mutant mice show normal LTP and learning abilities in the Morris water maze task, whereas adult (Ͼ13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by pharmacological inhibition of Rho-associated kinase (ROCK), a major downstream effector of Rho. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK and resultantly to enhanced LTP in the slice and learning impairments in the animal.

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Reduced Perisomatic Inhibition, Increased Excitatory Transmission, and Impaired Long-Term Potentiation in Mice Deficient for the Extracellular Matrix Glycoprotein Tenascin-R

Cited by 177 publications

References 47 publications

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

Hippocampal Metaplasticity Induced by Deficiency in the Extracellular Matrix Glycoprotein Tenascin-R

Age-Dependent Enhancement of Hippocampal Long-Term Potentiation and Impairment of Spatial Learning through the Rho-Associated Kinase Pathway in Protein Tyrosine Phosphatase Receptor Type Z-Deficient Mice

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