Understanding Hippocampal Development in Young Children With Autism Spectrum Disorder

Reinhardt, Vanessa P.; Iosif, Ana‐Maria; Libero, Lauren E.; Heath, Brianna; Rogers, Sally J.; Ferrer, Emilio; Nordahl, Christine Wu; Ghetti, Simona; Amaral, David G.; Solomon, Marjorie

doi:10.1016/j.jaac.2019.08.008

Cited by 54 publications

(46 citation statements)

References 43 publications

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“…In the hippocampus, DHEA is further metabolized to 7α-hydroxy-DHEA, which lower level was observed in this study. Interestingly, differences in the hippocampal asymmetry and mass have been already reported in ASD 54,55 . Moreover, reduced hippocampal connectivity during memory retrieval related to ASD was recently observed 56 .…”

Section: Discussionmentioning

confidence: 67%

Alteration of the steroidogenesis in boys with autism spectrum disorders

et al. 2020

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The etiology of autism spectrum disorders (ASD) remains unknown, but associations between prenatal hormonal changes and ASD risk were found. The consequences of these changes on the steroidogenesis during a postnatal development are not yet well known. The aim of this study was to analyze the steroid metabolic pathway in prepubertal ASD and neurotypical boys. Plasma samples were collected from 62 prepubertal ASD boys and 24 age and sex-matched controls (CTRL). Eighty-two biomarkers of steroidogenesis were detected using gas-chromatography tandem-mass spectrometry. We observed changes across the whole alternative backdoor pathway of androgens synthesis toward lower level in ASD group. Our data indicate suppressed production of pregnenolone sulfate at augmented activities of CYP17A1 and SULT2A1 and reduced HSD3B2 activity in ASD group which is partly consistent with the results reported in older children, in whom the adrenal zona reticularis significantly influences the steroid levels. Furthermore, we detected the suppressed activity of CYP7B1 enzyme readily metabolizing the precursors of sex hormones on one hand but increased anti-glucocorticoid effect of 7α-hydroxy-DHEA via competition with cortisone for HSD11B1 on the other. The multivariate model found significant correlations between behavioral indices and circulating steroids. From dependent variables, the best correlation was found for the social interaction (28.5%). Observed changes give a space for their utilization as biomarkers while reveal the etiopathogenesis of ASD. The aforementioned data indicate a direction of the future research with a focus on the expression and functioning of genes associated with important steroidogenic enzymes in ASD patients from early childhood to adrenarche.

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Section: Discussionmentioning

confidence: 67%

Alteration of the steroidogenesis in boys with autism spectrum disorders

et al. 2020

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“…For instance, enhanced connectivity and plasticity and increased structural synaptic markers [i.e., synaptophysin (SYN)] have been reported in VPA animals [ 38 , 41 , 42 ]. On the contrary, the hippocampus, a key structure of the limbic system implicated in exploration and social behavior [ 43 , 44 ], remains scarcely explored in VPA animals and also poorly understood in ASD [ 45 – 48 ]. Remarkably, a decrease in the dendritic tree of hippocampal neurons has been shown both in VPA animals and ASD patients [ 49 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders

et al. 2021

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Background Autism spectrum disorders (ASD) are synaptopathies characterized by area-specific synaptic alterations and neuroinflammation. Structural and adhesive features of hippocampal synapses have been described in the valproic acid (VPA) model. However, neuronal and microglial contribution to hippocampal synaptic pattern and its time-course of appearance is still unknown. Methods Male pups born from pregnant rats injected at embryonic day 10.5 with VPA (450 mg/kg, i.p.) or saline (control) were used. Maturation, exploratory activity and social interaction were assessed as autistic-like traits. Synaptic, cell adhesion and microglial markers were evaluated in the CA3 hippocampal region at postnatal day (PND) 3 and 35. Primary cultures of hippocampal neurons from control and VPA animals were used to study synaptic features and glutamate-induced structural remodeling. Basal and stimuli-mediated reactivity was assessed on microglia primary cultures isolated from control and VPA animals. Results At PND3, before VPA behavioral deficits were evident, synaptophysin immunoreactivity and the balance between the neuronal cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) were preserved in the hippocampus of VPA animals along with the absence of microgliosis. At PND35, concomitantly with the establishment of behavioral deficits, the hippocampus of VPA rats showed fewer excitatory synapses and increased NCAM/PSA-NCAM balance without microgliosis. Hippocampal neurons from VPA animals in culture exhibited a preserved synaptic puncta number at the beginning of the synaptogenic period in vitro but showed fewer excitatory synapses as well as increased NCAM/PSA-NCAM balance and resistance to glutamate-induced structural synaptic remodeling after active synaptogenesis. Microglial cells isolated from VPA animals and cultured in the absence of neurons showed similar basal and stimuli-induced reactivity to the control group. Results indicate that in the absence of glia, hippocampal neurons from VPA animals mirrored the in vivo synaptic pattern and suggest that while neurons are primed during the prenatal period, hippocampal microglia are not intrinsically altered. Conclusions Our study suggests microglial role is not determinant for developing neuronal alterations or counteracting neuronal outcome in the hippocampus and highlights the crucial role of hippocampal neurons and structural plasticity in the establishment of the synaptic alterations in the VPA rat model.

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“…In terms of neural substrates, altered hippocampal structure and function have been reported in ASD [Reinhardt et al, 2019]. It has also been reported that there is a correlation between autistic traits/symptomatology and gray matter density within the hippocampus [Salmond et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

“…Both atypical hippocampal structure and function have been found in ASD [DeLong, 1992; Reinhardt et al, 2019; Salmond et al, 2005]. Despite significant heterogeneity in ASD symptomatology, these previous findings motivate the hypothesis that individuals with ASD may exhibit specific differences compared to typically developing (TD) individuals in the relational binding processes that depend on hippocampal integrity and support rich and detailed episodic memories [Ben Shalom, 2003; Bowler, Gardiner, & Grice, 2000].…”

Section: Introductionmentioning

confidence: 99%

Children with ASD Show Impaired Item‐Space Recollection, But Preserved Item‐Color Recollection

et al. 2020

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Although individuals with autism spectrum disorder (ASD) have been often shown to display similar memory performance on semantic memory tasks compared to typically developing (TD) children, there is ongoing debate about whether and how their ability to remember specific past events (i.e., episodic memory) is impaired. We assessed a sample of 62 children with ASD and 72 TD children, ranging in age between 8 and 12 years on 2 memory tasks. Participants encoded a series of images and their association with either where they appeared on the screen (item-space association task) or with the color of an image's border (item-color association task). Children with ASD showed worse memory in the item-space association task compared to their TD peers, but comparable memory for the item-color association task. These differences persisted when age, intellectual quotient, and general item recognition memory were accounted for statistically. We interpret these results in light of evidence for specific deficits along the dorsal stream affecting processing of spatiotemporal information in ASD.

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Understanding Hippocampal Development in Young Children With Autism Spectrum Disorder

Cited by 54 publications

References 43 publications

Alteration of the steroidogenesis in boys with autism spectrum disorders

Alteration of the steroidogenesis in boys with autism spectrum disorders

Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders

Children with ASD Show Impaired Item‐Space Recollection, But Preserved Item‐Color Recollection

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