Molecular diversity of clustered protocadherin-α required for sensory integration and short-term memory in mice

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.

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…In brains of juvenile GABAergic Pcdhg mice, structures most notably reduced in volume include regions with proportionally higher GABAergic content, such as in basal ganglia and the midbrain. The behavioral deficits and seizures exhibited by GABAergic Pcdhg mutant mice point to broad GABAergic defects and further demonstrate the importance of cPcdhs in complex CNS patterning and behaviors Fukuda et al, 2008;Yamagishi et al, 2018). Cell type-and developmental-specific deletions are required to dissect additional roles for the Pcdhgs in GABAergic neuronal patterning, branching and maturation after PCD.…”

Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

“…In mice, for example, high likelihood of cPcdh matching is required for axonal tiling and assembly of serotonergic circuitries 56 . Further, mice genetically modified to increase the likelihood of cPcdh matching present abnormalities in higher cognitive functions in adult animals, interestingly, without grossly affecting fetal brain development 57 , and show higher levels of dendrite arborization 9 . On the contrary, low likelihood of cPcdh matching is required for proper axon convergence in the developing mouse olfactory system after birth 10 .…”

A Flexible Model of Working Memory

“…Second, the model predicts that disrupting random connectivity in the cortex should disrupt working memory performance. Indeed, recent results suggest this may be truemice with reduced diversity in protocadherins have impairments in sensory integration and short-term memory [Yamagishi et al, 2018]. At the single neuron level, the model would predict a reduction in the diversity of conjunctive representations in associative cortex when protocadherin diversity is impaired.…”