Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease

Attila D. Kovács, Angelika Saje, Andrew Wong, Gábor Szénási, Péter Kiricsi, Éva Szabó, Jonathan D. Cooper, David A. Pearce

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Mutations in the CLN3 gene cause juvenile Batten disease, a fatal pediatric neurodegenerative disorder. The Cln3-knockout (Cln3 Δex1-6) mouse model of the disease displays many pathological characteristics of the human disorder including a deficit in motor coordination. We have previously found that attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity in one-month-old Cln3 Δex1-6 mice resulted in an immediate improvement of their motor skills. Here we show that at a later stage of the disease, in 6-7-month-old Cln3 Δex1-6 mice, acute inhibition of AMPA receptors by a single intraperitoneal injection (1 mg/kg) of the non-competitive AMPA antagonist, EGIS-8332, does not have an immediate effect. Instead, it induces a delayed but prolonged improvement of motor skills. Four days after the injection of the AMPA antagonist, Cln3 Δex1-6 mice reached the same motor skill level as their wild type (WT) counterparts, an improvement that persisted for an additional four days. EGIS-8332 was rapidly eliminated from the brain as measured by HPLC-MS/MS. Histological analysis performed 8 days after the drug administration revealed that EGIS-8332 did not have any impact upon glial activation or the survival of vulnerable neuron populations in 7-month-old Cln3 Δex1-6 mice. We propose that temporary inhibition of AMPA receptors can induce a prolonged correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease.

Original languageEnglish
Pages (from-to)405-409
Number of pages5
JournalNeuropharmacology
Volume60
Issue number2-3
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Keywords

  • AMPA receptor
  • Cln3
  • EGIS-8332
  • Juvenile Batten disease
  • Neuronal ceroid lipofuscinoses
  • Rotarod

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