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Published on: February 15, 2015
Fyn is required for haloperidol-induced catalepsy in mice
Kotaro Hattori1, Shigeo Uchino, Tomoko Isosaka
1Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan. hattori@ncnp.go.jp
Abstract:
Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D(2) receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D(2) receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D(2) receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.
Insights
Fyn kinase deficiency reduces haloperidol-induced catalepsy and muscle rigidity in mice. This suggests Fyn
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Fyn kinase mediates tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits, impacting brain functions.
- NMDA receptor phosphorylation is linked to ethanol tolerance, learning, and seizure susceptibility.
Purpose of the Study:
- To investigate the role of Fyn kinase in haloperidol-induced catalepsy, an animal model for antipsychotic extrapyramidal side effects.
- To elucidate the molecular mechanisms underlying catalepsy.
Main Methods:
- Comparative study of haloperidol effects in control and Fyn-deficient mice.
- Western blotting to assess Fyn activation and NR2B subunit phosphorylation.
- Analysis of NMDA-induced calcium responses in cultured striatal neurons.
Main Results:
- Haloperidol induced catalepsy and rigidity in control mice, but significantly less in Fyn-deficient mice.
- Fyn activation and NR2B phosphorylation increased post-haloperidol in controls, but not in Fyn-deficient mice.
- Dopamine D(2) receptor blockade increased NR2B phosphorylation and NMDA-induced calcium responses in control neurons, but not Fyn-deficient neurons.
Conclusions:
- Fyn kinase plays a crucial role in mediating haloperidol-induced catalepsy.
- Haloperidol-induced catalepsy involves Fyn activation, subsequent NR2B phosphorylation, and altered striatal neuronal activity.
- This study proposes a novel molecular pathway for catalepsy involving dopamine D(2) receptor antagonism and Fyn signaling.
