TY - JOUR

T1 - Effects of the C.886C>T Mutation in the Mouse Tyrosine Hydroxylase Gene on Behavior and Dopamine System of the Brain

AU - Alsalloum, Ismail

AU - Rakhov, Ilya A.

AU - Komleva, Polina D.

AU - Kuranova, Valentina N.

AU - Bastrikova, Anastasia E.

AU - Kulikov, Alexander V.

AU - Bazovkina, Darya V.

N1 - Effects of the C.886C>T Mutation in the Mouse Tyrosine Hydroxylase Gene on Behavior and Dopamine System of the Brain / I. Alsalloum, I. A. Rakhov, P. D. Komleva [et al.] // Biochemistry (Moscow). – 2026. – Vol. 91, No. 7. – P. 1200-1215. – DOI 10.1134/S0006297926600171. – EDN REQWNK. This work was financially supported by the Russian Science Foundation (grant no. 25-25-00326). Animal housing was funded through the budgetary project FWNR-2026-0028.

PY - 2026/7/31

Y1 - 2026/7/31

N2 - Abstract: Dopamine (DA) is a critical regulator of physiological functions and adaptive behavior. The enzyme tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (DOPA), which is the first and rate-limiting step in the DA biosynthesis. Mutations in the human TH gene have been linked to dystonia, catalepsy, and catatonia. In the present study, we examined how the functional mutation c.886C>T in the Th gene affects the brain DA system and behavior in mice. The C allele – which confers high TH enzyme activity – was introgressed from the Mus musculus castaneus subspecies into the C57BL/6 inbred background, yielding three congenic genotypes: B6-886CC, B6-886CT, and B6-886TT. Males of each genotype were evaluated in a battery of behavioral tests; and TH activity, levels of DA and DA metabolites, norepinephrine, and mRNA levels of the key DA system genes were measured across the brain structures. The three genotypes did not differ in body weight, locomotor activity, motor coordination, or cognitive performance. However, the B6-886TT mice showed significantly reduced exploratory activity in the open field test relative to the B6-886CC and B6-886CT animals. The B6-886TT mice also exhibited lower TH activity and DA content in the midbrain, and reduced DOPAC levels in the hypothalamus, compared to the B6-886CC animals. The c.886C>T mutation had no detectable effect on expression of the genes encoding key DA metabolic enzymes or DA receptors. In a separate experiment, we genotyped 80 DNA samples from the Mus musculus collected across natural populations in Russia. The C and T allele frequencies were 0.981 and 0.019, respectively, suggesting that the T allele may be subject to negative natural selection.

AB - Abstract: Dopamine (DA) is a critical regulator of physiological functions and adaptive behavior. The enzyme tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (DOPA), which is the first and rate-limiting step in the DA biosynthesis. Mutations in the human TH gene have been linked to dystonia, catalepsy, and catatonia. In the present study, we examined how the functional mutation c.886C>T in the Th gene affects the brain DA system and behavior in mice. The C allele – which confers high TH enzyme activity – was introgressed from the Mus musculus castaneus subspecies into the C57BL/6 inbred background, yielding three congenic genotypes: B6-886CC, B6-886CT, and B6-886TT. Males of each genotype were evaluated in a battery of behavioral tests; and TH activity, levels of DA and DA metabolites, norepinephrine, and mRNA levels of the key DA system genes were measured across the brain structures. The three genotypes did not differ in body weight, locomotor activity, motor coordination, or cognitive performance. However, the B6-886TT mice showed significantly reduced exploratory activity in the open field test relative to the B6-886CC and B6-886CT animals. The B6-886TT mice also exhibited lower TH activity and DA content in the midbrain, and reduced DOPAC levels in the hypothalamus, compared to the B6-886CC animals. The c.886C>T mutation had no detectable effect on expression of the genes encoding key DA metabolic enzymes or DA receptors. In a separate experiment, we genotyped 80 DNA samples from the Mus musculus collected across natural populations in Russia. The C and T allele frequencies were 0.981 and 0.019, respectively, suggesting that the T allele may be subject to negative natural selection.

KW - behavior

KW - brain

KW - dopamine

KW - gene expression

KW - mice

KW - tyrosine hydroxylase

KW - тирозингидроксилаза

KW - дофамин

KW - мозг

KW - экспрессия генов

KW - поведение

KW - мыши

UR - https://www.mendeley.com/catalogue/a1ebfe7d-7c53-33ab-8d2b-79cb4e30e144/

UR - https://www.elibrary.ru/item.asp?id=91863542

UR - https://www.scopus.com/pages/publications/105046305850

U2 - 10.1134/S0006297926600171

DO - 10.1134/S0006297926600171

M3 - Article

C2 - 42633718

VL - 91

SP - 1200

EP - 1215

JO - Biochemistry (Moscow)

JF - Biochemistry (Moscow)

SN - 0006-2979

IS - 7

ER -