Abstract
Clustered protocadherins (Pcdhs) are neuronal cell adhesion molecules characterized by homophilic adhesion between the tetramers of 58 distinct isoforms in mice. The diversity of Pcdhs and resulting highly-specific neuronal adhesion may be required for the formation of neural circuits for executing higher brain functions. However, this hypothesis remains to be tested, because knockout of Pcdh genes produces abnormalities that may interfere with higher brain functions indirectly. In Pcdh-α1,12 mice, only α1, α12 and two constitutive isoforms are expressed out of 14 isoforms. The appearance and behavior of Pcdh-α1,12 mice are similar to those of wild-type mice, and most abnormalities reported in Pcdh-α knockout mice are not present in Pcdh-α1,12 mice. We examined Pcdh-α1,12 mice in detail, and found that cortical depression induced by sensory mismatches between vision and whisker sensation in the visual cortex was impaired. Since Pcdh-α is densely distributed over the cerebral cortex, various types of higher function are likely impaired in Pcdh-α1,12 mice. As expected, visual short-term memory of space/shape was impaired in behavioral experiments using space/shape cues. Furthermore, behavioral learning based on audio-visual associative memory was also impaired. These results indicate that the molecular diversity of Pcdh-α plays essential roles for sensory integration and short-term memory.
Highlights
Mouse models are powerful tools for investigating mental disorders[1], some of which are likely attributed to abnormalities in complex neural circuits required for executing higher brain functions
The appearance and behavior of Pcdh-α1,12 mice are similar to those of wild-type mice, and most abnormalities found in Pcdh-α knockout mice are not present in Pcdh-α1,12 mice, except for a particular type of cortical plasticity dependent on multimodal sensory integration[12]
These findings clearly indicate that diversity of Pcdh-α is required for executing higher cognitive functions including short-term memory and sensory integration, possibly because highly specific homophilic interactions between the tetramers of Pcdhs are required for specificity in Pcdh-dependent circuit formation together with growth of a properly complex dendrite arbor[17]
Summary
Mouse models are powerful tools for investigating mental disorders[1], some of which are likely attributed to abnormalities in complex neural circuits required for executing higher brain functions. A few isoforms in each gene cluster are randomly selected by stochastic expression at the individual neuron level, and the resulting diversity in Pcdhs is expected to play an important role in the formation of complex neural circuits[4,5,6], which possibly execute higher brain functions. These findings clearly indicate that diversity of Pcdh-α is required for executing higher cognitive functions including short-term memory and sensory integration, possibly because highly specific homophilic interactions between the tetramers of Pcdhs are required for specificity in Pcdh-dependent circuit formation together with growth of a properly complex dendrite arbor[17]
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