Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease

Attila D. Kovács, Angelika Saje, Andrew Wong, Serena Ramji, Jonathan D. Cooper, David A. Pearce

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3Δex1-6) mouse model recapitulates several features of the human disorder. Cln3Δex1-6 mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3Δex1-6 mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-d-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3Δex1-6 mice. At a later stage of the disease, in 6-7-month-old Cln3Δex1-6 mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3Δex1-6 mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease.

Original languageEnglish
Pages (from-to)769-775
Number of pages7
JournalNeuropharmacology
Volume63
Issue number5
DOIs
StatePublished - Oct 2012

Keywords

  • AMPA receptor
  • Cln3
  • Juvenile Batten disease
  • NMDA receptor
  • Neuronal ceroid lipofuscinoses
  • Rotarod

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