Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.
A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene
lignans have been synthesized and
evaluated for their ability to selectively inhibit PDE IV isolated from
guinea pig. Replacement
of the 1-phenyl ring by a pyridone ring led to marked improvement of
their selectivity for PDE
IV over PDE III. The compounds that were most potent and selective
involved those bearing
an N-alkylpyridone ring at C-1. These compounds also
showed potent antispasmogenic activity
without causing significant changes in heart rate in the guinea pig.
The most potent compound
was
6,7-diethoxy-2,3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]naphthalene
(17f), ED50 values of histamine-induced and
antigen-induced bronchoconstriction in the guinea
pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was
chosen as a candidate for
further pharmacological evaluation.
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