Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease.
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 (1mg/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.
Center for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Attila D
AD
Kovács
Angelika
A
Saje
Andrew
A
Wong
Gábor
G
Szénási
Péter
P
Kiricsi
Eva
E
Szabó
Jonathan D
JD
Cooper
David A
DA
Pearce
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
C505036:EGIS-8332; D018091:Receptors, AMPA; D001569:Benzodiazepines