Reduced expression of tryptophan hydroxylase in the prefrontal cortex of a parkinsonian mouse model

Abstract

OBJECTIVEIn 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated mouse model of Parkinson's disease (PD), we have shown a significant decrease in the density of beaded type serotonin (5‐HT) axons and concentrations of 5‐HT in the prefrontal cortex (PFC). Here we studied the protein level of tryptophan hydroxylase (TPH) and beta arrestin (βAR) 1 and 2 in the PFC in MPTP treated mice.DESIGN AND METHODSMale C57BL/6J mice were treated with 4 doses of MPTP 20 mg/kg (i.p.) at every 2 hours and sacrificed after 3 and 16 weeks. The protein expression for TPH, βAR‐1 and ‐2 in the PFC and TPH in the raphe was studied by Western blot. 5‐HT cell bodies in the raphe were studied by immunohistochemistry.RESULTSMPTP‐treated mice have shown a significant decrease in TPH protein level in PFC and a significant increase in the raphe nucleus. Protein expression for β‐AR1 and β‐AR2 were also significantly decreased in PFC. Immunohistochemistry of 5‐HT neurons in the raphe nuclei with TPH antibodies showed reduced intensity of staining for 5‐HT cell bodies in medial raphe (MR) and slightly increased in dorsal raphe (DR) after MPTP treatment. The reduced density of TPH‐labeled 5‐HT neurons in the MR correlated well with our earlier report of preferential decrease in the density of thick beaded 5‐HT axons in the PFC which originate from MR.CONCLUSIONThese results suggest that TPH is a major target of MPTP‐induced alterations of serotonergic function in PFC with a possible link to depression. Targeting TPH and related signaling events may afford therapeutic advantages for the management of depression in PD. Supported by NIH SNRP/NINDS grant NS041071.