Motor Deficits Coupled to Cerebellar and Striatal Alterations in Ube3am-/p+ Mice Modelling Angelman Syndrome Are Attenuated by Adenosine A2A Receptor Blockade

Abstract

Angelman syndrome (AS) is a neurogenetic disorder involving ataxia and motor dysfunction, resulting from the absence of the maternally inherited functional Ube3a protein in neurons. Since adenosine A_2A receptor (A_2AR) blockade relieves synaptic and motor impairments in Parkinson's or Machado-Joseph's diseases, we now tested if A_2AR blockade was also effective in attenuating motor deficits in an AS (Ube3a^m-/p+) mouse model and if this involved correction of synaptic alterations in striatum and cerebellum. Chronic administration of the A_2AR antagonist SCH58261 (0.1 mg/kg/day, ip) promoted motor learning of AS mice in the accelerating-rotarod task and rescued the grip strength impairment of AS animals. These motor impairments were accompanied by synaptic alterations in cerebellum and striatum typified by upregulation of synaptophysin and vesicular GABA transporters (vGAT) in the cerebellum of AS mice along with a downregulation of vGAT, vesicular glutamate transporter 1 (vGLUT1) and the dopamine active transporter in AS striatum. Notably, A_2AR blockade prevented the synaptic alterations found in AS mice cerebellum as well as the downregulation of striatal vGAT and vGLUT1. This provides the first indications that A_2AR blockade may counteract the characteristic motor impairments and synaptic changes of AS, although more studies are needed to unravel the underlying mechanisms.

Keywords: Adenosine A2A receptor; Angelman syndrome; Cerebellum; Motor function; Striatum; Ube3a.