Genetic mutations in Ca²⁺ signaling alter dendrite morphology and social approach in juvenile mice

Abstract

Dendritic morphology is a critical determinant of neuronal connectivity, and calcium signaling plays a predominant role in shaping dendrites. Altered dendritic morphology and genetic mutations in calcium signaling are both associated with neurodevelopmental disorders (NDDs). In this study we tested the hypothesis that dendritic arborization and NDD-relevant behavioral phenotypes are altered by human mutations that modulate calcium-dependent signaling pathways implicated in NDDs. The dendritic morphology of pyramidal neurons in CA1 hippocampus and somatosensory cortex was quantified in Golgi-stained brain sections from juvenile mice of both sexes expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I-RYR1), a human CGG repeat expansion (170-200 CGG repeats) in the fragile X mental retardation gene 1 (FMR1 premutation), both mutations (double mutation; DM), or wildtype mice. In hippocampal neurons, increased dendritic arborization was observed in male T4826I-RYR1 and, to a lesser extent, male FMR1 premutation neurons. Dendritic morphology of cortical neurons was altered in both sexes of FMR1 premutation and DM animals with the most pronounced differences seen in DM females. Genotype also impaired behavior, as assessed using the three-chambered social approach test. The most striking lack of sociability was observed in DM male and female mice. In conclusion, mutations that alter the fidelity of calcium signaling enhance dendritic arborization in a brain region- and sex-specific manner and impair social behavior in juvenile mice. The phenotypic outcomes of these mutations likely provide a susceptible biological substrate for additional environmental stressors that converge on calcium signaling to determine individual NDD risk.

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…These include mice engineered to express human MH mutations in Ryr1 [192,193] or the human CGG repeat expansion in the premutation range in the fragile X mental retardation (Fmr1) gene [156]. Relative to congenic wild-type controls, mice that express these mutations exhibit altered dendritic morphology in hippocampal and cortical neurons coincident with altered social behavior [194]. The effects on dendritic arborization phenocopy the effects observed with developmental PCB exposure alone [116].…”

Developmental exposure to polychlorinated biphenyls (PCBs) in the maternal diet causes host-microbe defects in weanling offspring mice

“…Similarly, PCB 126 exposure to adult mice caused reductions in alpha diversity coupled with decreases in levels of the beneficial genera Bifidobacteria and Lactobacillus (Petriello et al, 2018). Here we establish that developmental exposure to an environmentally relevant mixture of PCBs via the maternal diet results in intestinal dysbiosis and altered GI physiology in juvenile offspring that are genetically susceptible to neurobehavioral impairments (Keil et al, 2019). Together, these data demonstrate that in a mouse model expressing multiple mutations shown to produce abnormal Ca 2þ dynamics in neurons, also exhibits GI pathophysiology and dysbiosis of the GI microbiome, which is further impaired following developmental PCB exposure.…”

“…This study utilized mice expressing a human gain-of-function mutation in RyR1 (T4826I-RYR1) and a human CGG repeat expansion (170e200 CGG repeats) in the FMR1 gene (premutation range), which are referred to as the double mutant [DM] mice, or congenic wildtype (WT: 75% C57BL/6; 25% Sv129 as determined by SNP analysis) mice. The DM mouse was previously described (Keil et al, 2019). CGG repeat lengths were confirmed using Expanded High Fidelity Plus PCR System (Roche Diagnostics, Indianapolis, IN) as described previously .…”

“…In mice expressing FMR1 CGG expansions <200 repeats (a model of FMR1 premutation) were shown to have chronically elevated cytoplasmic resting Ca 2þ and mcalpain activity in premutation neurons (Robin et al, 2017). Coexpression of these two mutations has recently been found to confer social behavioral deficits as well as increased hippocampal dendritic arborization in juvenile mice compared to wild type congenic control mice (Keil et al, 2019).…”

Neurotoxicity of polychlorinated biphenyls and related organohalogens

“…Morphometric analyses of pyramidal neurons in various cortical regions altered in ASD, has revealed increased dendritic complexity, including increased dendritic spines [76,79], on projection neurons. While studies from the 1990s indicated less complex dendritic arborization in the hippocampus of subjects with ASD [193], more recent studies of genetic mouse models of ASD have identified increased dendritic complexity of hippocampal neurons [27,85,90].…”