B12 The influence of kalirin-7 deficiency on the phenotype of YAC128 mice

Abstract

<h3>Background</h3> The guanine-nucleotide exchange factor kalirin is a key regulator of spine morphogenesis and important for synaptic function and glutamatergic transmission. <i>Kalirin-7</i>-knockout mice (Kal7KO) deficient for the most abundant isoform of <i>kalirin</i> in the adult brain show a decrease in hippocampal spine density and specific behavioural changes. In Huntington9s disease (HD) there is evidence for abnormalities in synaptic plasticity and transmission in several brain regions in patients and mouse models. These alterations are supposed to account for cognitive and motoric deficits in HD. <h3>Aims</h3> To analyse the interaction between Huntingtin and proteins involved in synaptic plasticity in vivo on a behavioural and molecular level we generated a mouse model lacking <i>kalirin-7 (Kal7)</i> while overexpressing the human <i>huntingtin (htt)</i> with 128 CAGs (YAC128). The YAC128 mice show motor deficits, cognitive impairment and a striatal degeneration reproducing symptoms of the human disease. <h3>Methods</h3> The Kal7KO-YAC128 mouse model was first analysed in a set of behavioural tests. Kal7KO-YAC128 mice were compared with littermates heterozygous for <i>htt</i> (YAC128), homozygous deficient for <i>Kal7</i> (Kal7KO) and wildtype controls. 13–15 males of each group were repeatedly tested from 4 to 15 months in Rotarod, Simple swimming test, Elevated plus maze (EPM) and the automated home cage system LabMaster (LM; TSE Systems). The influence of <i>kalirin-7</i> deficiency on the expression of mutant huntingtin, the glutamatergic NMDA receptor subunits NR1, NR2A and NR2B as well as on the level of synaptic proteins like PSD-95 were analysed by immunoblotting and immunohistochemistry in cortex, striatum and hippocampus. Moreover we examined in the same brain regions the morphology of neurons and the synaptic morphology by electron microscopy. <h3>Results</h3> The motoric deficit of the YAC128 was not changed by the Kalirin 7-deficiency. No significant difference in anxiety could be found between YAC128 and Kal7KO-YAC128. Results of the Simple swimming test and LM are still under analysis. First results of the biochemical analysis are going to be presented. <h3>Conclusions</h3> Preliminary results indicate that <i>kalirin-7</i> deletion does not influence the behavioural phenotype of YAC128 mice.