TY - JOUR
T1 - Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype
AU - Nietz, Angela
AU - Krook-Magnuson, Chris
AU - Gutierrez, Haruna
AU - Klein, Julia
AU - Sauve, Clarke
AU - Hoff, Isaac
AU - Wick, Zoé Christenson
AU - Krook-Magnuson, Esther
N1 - Publisher Copyright:
0022-3077/20 Copyright © 2020 the American Physiological Society
PY - 2020/10
Y1 - 2020/10
N2 - Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABAAa1 subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABAAa1 subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor. Purkinje cell specific knockout of the GABAAa1 subunit abolished all GABAA-mediated inhibition in Purkinje cells, while leaving GABAA-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABAAa1 from Purkinje cells did not produce deficits on the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABAAa1 subunit, and, like essential tremor in patients, was responsive to ethanol. These findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells in tremor. NEW & NOTEWORTHY Animals with a global knockout of the GABAAa1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABAAa1 from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.
AB - Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABAAa1 subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABAAa1 subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor. Purkinje cell specific knockout of the GABAAa1 subunit abolished all GABAA-mediated inhibition in Purkinje cells, while leaving GABAA-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABAAa1 from Purkinje cells did not produce deficits on the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABAAa1 subunit, and, like essential tremor in patients, was responsive to ethanol. These findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells in tremor. NEW & NOTEWORTHY Animals with a global knockout of the GABAAa1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABAAa1 from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.
KW - Alcohol
KW - Cerebellum
KW - Essential tremor
KW - GABA
KW - Inhibition
UR - http://www.scopus.com/inward/record.url?scp=85093901835&partnerID=8YFLogxK
U2 - 10.1152/jn.00100.2020
DO - 10.1152/jn.00100.2020
M3 - Article
C2 - 32902350
AN - SCOPUS:85093901835
SN - 0022-3077
VL - 124
SP - 1183
EP - 1197
JO - Journal of Neurophysiology
JF - Journal of Neurophysiology
IS - 4
ER -