Heterogeneity between hippocampal and septal astroglia as a contributing factor to differential in vivo AMPA excitotoxicity

Abstract

Astroglial participation in the regional differences of vulnerability to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced neurodegeneration was investigated in the rat hippocampus and medial septum using L-alpha-aminoadipate (alpha-AA) as a specific astroglial toxin. alpha-AA was microinjected in the hippocampus and the medial septum and a time-course study was carried out between 2 hr and 3 days. When compared to controls, microinjection of alpha-AA in the hippocampus induced within 3 days a reversible loss of glial fibrillary acidic protein (GFAP) immunostaining and a microglial reaction without any neuronal loss, whereas in the medial septum it caused no effects on astroglial, microglial, or neuronal populations. Differences in hippocampus and medial septum vulnerability were also evidenced when alpha-AA was co-injected with AMPA and neurodegeneration was assessed in terms of neuronal loss, glial reactions, calcification, and atrophy of the area. In the hippocampus, alpha-AA increased AMPA excitotoxicity with marked disorganization of all hippocampal subfields, increased neuronal loss, a more important astroglial reaction, a larger area of microgliosis, and a greater abundance of calcium deposits. By contrast, in the medial septum alpha-AA did not modify any parameter of the AMPA-induced lesion. In conclusion, the presence of different astroglial populations in hippocampus and medial septum results in a different participation to AMPA excitotoxicity that may determine, at least in part, the specific regional vulnerability to neurodegeneration.

A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance

“…11a). In agreement with previous studies (Khurgel et al, 1996;Rodriguez et al, 2004), L-␣-AA (50 nmol) produced a marked reduction of GFAP-positive astrocytes in the dorsal horn (Fig. 11b,c).…”

“…However, L-␣-AA did not affect the number of NeuN-positive neurons in the spinal cord (Fig. 11d,e), in support of previous studies (Khurgel et al, 1996;Rodriguez et al, 2004), nor did L-␣-AA alter the basal pain sensitivity in uninjured animals even at a high dose (150 nmol); the mechanical threshold was 15.7 Ϯ 2.5, 16.0 Ϯ 4.1, and 15.4 Ϯ 2.8 g before and at 6 and 24 h after intrathecal L-␣-AA injection (150 nmol), respectively ( p Ͼ 0.05; n ϭ 5).…”

“…Ultrastructural evidence suggests that degeneration is confined to astrocytes after the injection of this toxin into the striatum (Huck et al, 1984;Khurgel et al, 1996;Rodriguez et al, 2004). To further examine whether spinal astrocytes are important for neuropathic pain, we administrated L-␣-AA intrathecally to SNL rats on postoperative day 10.…”

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…1). In agreement with previous studies (Khurgel et al, 1996;Rodriguez et al, 2004), L-α-AA produces a marked reduction of GFAP-positive astrocytes in the dorsal horn but has no effect on NeuN-positive spinal neurons (Zhuang et al, 2006a). The anti-allodynic effect of the toxin is reversible, recovering after 3 days (Fig.…”

“…L-alphaaminoadipate (L-α-AA) is a cytotoxin that is relatively specific for astrocytes. Ultrastructural studies indicate that cell degeneration is confined to astrocytes following the injection of this toxin into the striatum (Huck et al, 1984;Khurgel et al, 1996;Rodriguez et al, 2004). Intrathecal injection of L-α-AA to spinal nerve-ligated rats produces a dose-dependent attenuation of mechanical allodynia, which is a major symptom of chronic pain (Fig.…”