title: Enhanced synaptic inhibition in the cerebellar cortex of the ataxic PMCA2(-/-) knockout mouse.
abstract: Mice with genetic deletion of a calcium extrusion pump, the plasma membrane calcium ATPase isoform 2, PMCA2, exhibit overt cerebellar ataxia, but the cellular mechanisms are only partially understood. Here, we report an enhanced synaptic GABAergic inhibition within the molecular layer of cerebellar cortex slices from PMCA2 knockout (PMCA2(-/-)) mice, a finding that could contribute to the observed ataxia. Purkinje neurons from PMCA2(-/-) mice exhibited an increased frequency and amplitude of spontaneous inhibitory post-synaptic currents that was accompanied by an enhanced spontaneous firing frequency of molecular layer interneurons (both basket cells and stellate cells). The elevated inhibition was sufficient to reduce the frequency and regularity of spike firing by PMCA2(-/-) Purkinje neurons. Acute pharmacological inhibition of PMCA recapitulated some of these features in wild-type mice indicating that the changes were in part a direct result of PMCA2 removal. However, additional compensatory mechanisms within the PMCA2(-/-) mouse were also a major factor. Indeed, morphological studies revealed an abnormally large number of molecular layer interneurons (basket cells and stellate cells) and GABAergic synapses within the PMCA2(-/-) cerebellar cortex. We conclude that loss of PMCA2 adversely influences the function and organisation of Purkinje neuron synaptic inhibition as a major contributory mechanism to the ataxic phenotype of the PMCA2(-/-) mouse.
authors.affiliation: Department of Physiology, Brain Health Research Centre, University of Otago School of Medical Sciences, Dunedin, New Zealand. ruth.empson@otago.ac.nz
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Empson
authors.forename: Helena
authors.initials: H
authors.lastname: Huang
authors.forename: Raghavendra Y
authors.initials: RY
authors.lastname: Nagaraja
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Roome
authors.forename: Thomas
authors.initials: T
authors.lastname: Knöpfel
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse