The results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.
Abstract
Abstract β-catenin-coding gene CTNNB1 is a top-ranking risk gene for autism and intellectual disability. To better understand how CTNNB1 haploinsufficiency is involved in the pathophysiology of neurodevelopmental disorders, we generated a new mouse model that enables Ctnnb1 deletion in forebrain excitatory neurons starting at embryonic corticogenesis. Behavioural assays of the Ctnnb1 conditional knockout (cKO) mice revealed significant fear memory deficits, despite normal social preference, anxiety, spatial and recognition memory. Pyramidal neurons in prefrontal cortex (PFC) of Ctnnb1 cKO mice exhibited the significantly elevated intrinsic excitability but markedly decreased AMPA receptor-mediated synaptic response, while GABAA or NMDA receptor-mediated synaptic response was unchanged. Gene profiling revealed the significantly reduced mRNA level of Syp (encoding Synaptophysin) and Nlng2 (encoding Neuroligin-2) in PFC of Ctnnb1 cKO mice, while most of other screened genes were unchanged. These results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.
These findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.
Sehyoun Yoon, Marc Dos Santos, Natalia Khalatyan et al.· Proceedings of the National...· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
This study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways and provides a foundation for understanding the role of KIF2C in neural development.
It is demonstrated that Ddit4 overexpression specifically in neurons is sufficient to reduce spine density in the PFC, impair temporal order memory, and induce transcriptional changes associated with stress and depression.
Alexander M. Kuhn, Kelly E. Bosis, Madeline M Mairose et al.· eNeuro· 0 citations
In mice with conditional Arid1b haploinsufficiency in excitatory neurons, an increase in the rate of synaptic connectivity between excitatory neurons and reduced strength of excitatory synapses to parvalbumin (PV)-expressing inhibitory interneurons is found.
Alec H. Marshall, Meretta A. Hanson, Danielle J. Boyle et al.· Experimental Neurology· 0 citations
Protein kinase C alpha (PKCα), encoded by Prkca, has been implicated in neuronal signaling, plasticity, and memory. Human genetic studies identify PRKCA as a candidate locus relevant to memory and posttraumatic stress disorder (PTSD), but the physiological functions of PKCα remain incompletely defined. Here, we examined the anatomical distribution, signaling function, and behavioral phenotypes associated with constitutive global PKCα deficiency in Prkca-/- mice. PKCα was enriched in forebrain regions, including the hippocampus and prefrontal cortex. It was detected in MAP2-positive neurons and was not detected in GFAP-positive astrocytes. In cultured hippocampal neurons, PKC activation induced redistribution of PKCα to dendritic and membrane-associated compartments, including PSD95-positive postsynaptic sites. PKCα deficiency did not alter gross hippocampal morphology or the basal abundance of major neuronal and synaptic marker proteins, but it reduced basal phosphorylation of pan-PKC, CaMKIIα, and the AMPA receptor subunit GluR1 at Ser831. Male Prkca-/- mice showed impaired hippocampus-dependent spatial memory, increased anxiety-like behavior, and a marked deficit in contextual fear extinction. These findings identify PKCα as part of a signaling program associated with synaptic function and support a role for PKCα-dependent processes in adaptive updating of learned fear.
Lulu An, Miyoung Yang, Qi Ding et al.· Neurobiology of Stress· 0 citations
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