N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo

Abstract

N-cadherin and β-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, β-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/β-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function.

Cadherins and catenins in dendrite and synapse morphogenesis

“…38 Similar results were observed in mice in which N-cadherin was genetically ablated in late postnatal forebrain synapses. 48 However, in this case, the levels of the GluA1 receptor and PSD95, an excitatory postsynaptic scaffolding protein, were decreased. Interestingly, these changes were accompanied by an increase in the density of inhibitory synapse markers, suggesting a role for Ncadherin in maintaining an appropriate balance between excitatory and inhibitory synapses.…”

Maturation of cortical circuits requires Semaphorin 7A

“…Data were imaged on a Zeiss Axiophot, Zeiss LSM 510, or Zeiss LSM 780 microscope. Brain lysates and synaptoneurosomes were prepared from dissections of S1 or thalamus (41,42).…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…Inactivation of CDH2 in the dorsal telencephalon results in a "double cortex" phenotype, with heterotopic gray matter interposed between zones of white matter [Gil-Sanz et al, 2014]. CDH2 indeed regulates the proliferation and differentiation of ventral midbrain dopaminergic progenitors, the organization of excitatory and inhibitory synaptic circuits, and long-term potentiation in the adult hippocampus [Bozdagi et al, 2010;Sakane and Miyamoto, 2013;Nikitczuk et al, 2014]. The gene was found to be mutated in schizophrenics in a whole-exome sequencing study .…”