Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS

Lo, Fu‐Sun; Zhao, Shuxin; Erzurumlu, Reha S.

doi:10.1152/jn.00312.2011

Cited by 32 publications

(37 citation statements)

References 82 publications

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“…Future studies will more directly examine whether the effects of GBP reported here are due to interruption of TSP/α2δ-1 signaling. Although the mechanism for these effects remains uncertain, changes in TSP/α2δ-1-driven excitatory synaptogenesis have been suggested to mediate the therapeutic effects of GBP in several injury models (Li et al, 2012; Lo et al, 2011) and may play a role in the protective effects of GBP in the FL cortex.…”

Section: Discussionmentioning

confidence: 99%

“…Rather, its therapeutic actions appear to be mediated by antagonizing the interaction of TSP and α2δ-1 (Eroglu et al, 2009; Eroglu, 2009). Recent studies have shown that GBP treatment prevented injury-induced increases in reactive astrocytosis and excitatory synaptogenesis (Li et al, 2012; Lo et al, 2011). Furthermore, GBP treatment attenuated cortical hyperexcitability in a model of posttraumatic epilepsy associated with upregulation of α2δ-1 (Li et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Lau

Hampton

Taylor-Weiner

et al. 2014

Neurobiology of Disease

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Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/ α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/ α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Lau

Hampton

Taylor-Weiner

et al. 2014

Neurobiology of Disease

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“…Recently, new silent synapses were found in the adult brain after exposure to cocaine (Huang et al, 2009;Koya et al, 2012), trauma (Lo et al, 2011), chronic stress (Suvrathan et al, 2014), or during aging (Sametsky et al, 2010). Their formation involves de novo synaptogenesis and (or) removal of AMPAR from regular synapses (Hanse et al, 2013).…”

Section: Formation and Role Of Silent Synapsesmentioning

confidence: 99%

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

Ito

Erişir

Morozov

2015

Neuropsychopharmacol

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Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.

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“…Although increases in synapse number are observed in the dorsal horn in neuropathic pain states (Jaken et al, 2010; Lin et al, 2011; Peng et al, 2010), the spinal signals initiating synaptogenesis remain unclear. One family of extracellular matrix proteins, the thrombospondins (TSPs), promotes synaptogenesis (Christopherson et al, 2005; Eroglu et al, 2009; Lo et al, 2011). The thrombospondins are glycoproteins that are produced by numerous cell types and have widely varying roles in cell signaling (Adams, 2001; Adams and Lawler, 2004).…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury

Crosby

Zaucke

Kras

et al. 2015

Experimental Neurology

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Facet joint injury induces persistent pain that may be maintained by structural plasticity in the spinal cord. Astrocyte-derived thrombospondins, especially thrombospondin-4 (TSP4), have been implicated in synaptogenesis and spinal sensitization in neuropathic pain, but the TSP4 response and its relationship to synaptic changes in the spinal cord have not been investigated for painful joint injury. This study investigates the role of TSP4 in the development and maintenance of persistent pain following injurious facet joint distraction in rats and tests the hypothesis that excitatory synaptogenesis contributes to such pain. Painful facet joint loading induces dorsal horn excitatory synaptogenesis along with decreased TSP4 in the DRG and increased astrocytic release of TSP4 in the spinal cord, all of which parallel the time course of sustained tactile allodynia. Blocking injury-induced spinal TSP4 expression with antisense oligonucleotides or reducing TSP4 activity at its neuronal receptor in the spinal cord with gabapentin treatment both attenuate the allodynia and dorsal horn synaptogenesis that develop after painful facet joint loading. Increased spinal TSP4 also facilitates the development of allodynia and spinal hyperexcitability, even after non-painful physiologic loading of the facet joint. These results suggest that spinal TSP4 plays an important role in the development and maintenance of persistent joint-mediated pain by inducing excitatory synaptogenesis and facilitating the transduction of mechanical loading of the facet joint that leads to spinal hyperexcitability.

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Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS

Cited by 32 publications

References 82 publications

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury

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