Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism

Abstract

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.

Saturated reconstruction of living brain tissue

“…The mean density of spines was 1.7/µm dendrite length. Both, length and density quantifications are in-keeping with previous data 38 . Fig.…”

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

“…These mice show several ASD-like behaviours, but the genetic basis of neuronal circuit dysfunction is unclear. However single nucleotide polymorphisms in genes for dendritic proteins including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11) have been reported, suggestive of impaired dendritic function at glutamatergic synapses (Barón-Mendoza et al ., 2021). Both repetitive and social interaction deficits in C58 mice were mitigated by mGluR5 negative allosteric modulation (Silverman et al ., 2012).…”

Changes in neuroinflammatory markers and microglial density in the hippocampus and prefrontal cortex of the C58/J mouse model of autism

“…The C58/J inbred mouse strain displays a low social preference and stereotyped behaviors (Muehlmann et al, 2012;Ryan et al, 2010), and it is suitable for modeling idiopathic autism. Adult male mice of this strain have a decreased dendritic arbor complexity in the hippocampus and in the PFC (Bar on-Mendoza et al, 2019), along with fewer dendritic spines with a mature-like morphology in the CA1 hippocampal region and a lower dendritic spine density in the PFC (Bar on-Mendoza et al, 2021).…”

“…Furthermore, this mouse strain bears multiple single nucleotide polymorphisms (SNPs) in several genes related to different cellular and molecular functions, such as cytoskeleton remodeling and synaptic transmission, some of which have orthologous genes in humans that have been linked to an increased risk for autism (Bar on-Mendoza et al, 2021;Moy et al, 2014), albeit no inflammatory alterations have been explored in this mouse model.…”

“…The C58/J inbred mouse strain displays a low social preference and stereotyped behaviors (Muehlmann et al, 2012; Ryan et al, 2010), and it is suitable for modeling idiopathic autism. Adult male mice of this strain have a decreased dendritic arbor complexity in the hippocampus and in the PFC (Barón‐Mendoza et al, 2019), along with fewer dendritic spines with a mature‐like morphology in the CA1 hippocampal region and a lower dendritic spine density in the PFC (Barón‐Mendoza et al, 2021). Furthermore, this mouse strain bears multiple single nucleotide polymorphisms (SNPs) in several genes related to different cellular and molecular functions, such as cytoskeleton remodeling and synaptic transmission, some of which have orthologous genes in humans that have been linked to an increased risk for autism (Barón‐Mendoza et al, 2021; Moy et al, 2014), albeit no inflammatory alterations have been explored in this mouse model.…”