Huntington’s disease (HD) is an autosomal-dominant inherited disease resulting from expanded amino acid (CAG) repeat in the gene that encodes protein huntingtin (Htt), currently incurable. It causes the progressive degeneration of nerve cells in the brain. A lot of evidence implicates aberrant synaptic connection between cortical and striatal neurons, a key component of HD pathology, which also leads to cognitive decline and motor disorders. Synaptic activity between cortical and striatal neurons was studied using in vitro model of cocultured cortico-striatal neurons. Cell culture was obtained from the brain of mice YAC 128 coding mutation, causing HD. Primary abnormalities were revealed on the day 14 in vitro cultivation of neuronal cell culture. Neurons from YAC128 mice were characterized by spontaneous activity compared with wild type. At the same time there were no differences in spine morphology of striatal neurons on the day 14 in vitro, but using novel optogenetic approach synaptic contacts dysfunction were demonstrated in YAC128 culture. On the day 19 in vitro cultivation the activity of YAC128 cortical neurons was reduced which possibly resulted in postsynaptic disturbance – spine elimination and changing of spine morphology, which could possibly be a main reason of neurodegeneration during HD development. This work was supported by the contract with the Russian Ministry of Science 11.G34.31.0056 (Ilya Bezprozvanny).