Implication of Hippocampal Neurogenesis in Autism Spectrum Disorder:
Pathogenesis and Therapeutic Implications

Liu, Chuanqi; Liu, Jiayin; Gong, Hong; Liu, Tianyao; Li, Xin; Xiaotang, FAN

doi:10.2174/1570159x21666221220155455

Cited by 15 publications

(16 citation statements)

References 183 publications

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“…Therefore, changes in the E-I balance that are suggested to occur in neurodevelopmental disorders (Gao and Penzes, 2015;Kenny et al, 2022) may influence physiological generation of SWRs. Interestingly, previously accumulated evidence shows that FXS-associated neurobiological changes are brain region-specific (Anagnostou and Taylor, 2011;Varghese et al, 2017;Fetit et al, 2021) and hippocampus is among the brain regions that are affected by the loss of FMRP (Banker et al, 2021;Liu et al, 2022). However, the hippocampus is a functionally heterogeneous structure in both health and disease (Bannerman et al, 2014;Strange et al, 2014) and the dorsal and the ventral hippocampus are differently implicated in neuropsychiatric and neurodevelopmental disorders; reviewed by Sahay and Hen (2007), Tanti and Belzung (2013), Bartsch and Wulff (2015), Gulyaeva (2019), and Bakoyiannis et al (2023).…”

Section: Introductionmentioning

confidence: 99%

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

Leontiadis,

Trompoukis,

Tsotsokou

et al. 2023

Front. Cell. Neurosci.

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Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.

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Section: Introductionmentioning

confidence: 99%

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

Leontiadis,

Trompoukis,

Tsotsokou

et al. 2023

Front. Cell. Neurosci.

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“…Moreover, MOR modulates the hippocampal neurogenesis, mediating a negative opioid effect, whereas a positive effect can be seen in MOR null knock-out mice [79, 80]. The animal models of ASD present an impaired hippocampal neurogenesis, possibly explaining some of the behavioral phenotypes of the disorder [81]. Our findings on MOR availability could relate to these forementioned behavioral impairments and aberrant modulation of the DMN and the possibly impaired hippocampal neurogenesis in ASD.…”

Section: Discussionmentioning

confidence: 76%

Dopamine D2R and opioid MOR availability in autism spectrum disorder

Noppari,

Tuisku,

Lukkarinen

et al. 2024

Preprint

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Opioid and dopamine receptor systems are implicated in the pathoetiology of autism, but in vivo human brain imaging evidence for their role remains elusive. Here, we investigated regional type 2 dopamine and mu-opioid receptor (D2R and MOR, respectively) availabilities and regional interactions between the two neuromodulatory systems associated with autism spectrum disorder (ASD). In vivo positron emission tomography (PET) with radioligands [11C]raclopride (D2R) and [11C]carfentanil (MOR) was carried out in 16 adult males with high functioning ASD and 19 age and sex matched controls. Regional group differences in D2R and MOR receptor availabilities were tested with linear mixed models and associations between regional receptor availabilities were examined with correlations. There were no group differences in whole-brain voxel-wise analysis of DR2 but ROI analysis presented a lower overall mean D2R availability in striatum of the ASD versus control group. Post hoc regional analysis revealed reduced D2R availability in nucleus accumbens of the ASD group. The whole-brain voxel-wise analysis of MOR revealed precuneal up-regulation in the ASD group, but there was no overall group difference in the ROI analysis for MOR. MOR down-regulation was observed in the hippocampi of the ASD group in a post hoc analysis. Regional correlations between D2R and MOR availabilities were weaker in the ASD group versus control group in the amygdala and nucleus accumbens. These alterations may translate to disrupted modulation of social motivation and reward in ASD.

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“…In this regard, our results showed that BTBR animals had decreased NGF and BDNF expression levels in HIPP, a brain region in which such neurotrophins are mainly present [ 88 ]. Accordingly, hippocampal BDNF and NGF deficiency has been associated with ASD development [ 89 , 90 ], however results are contrasting, since BDNF brain levels fluctuations have been reported in response to several known, such as brain areas and age, and unknown factors [ 91 ]. In addition, NGF levels were reduced also in AMY, a brain region in which NGF signalling has been linked to stress, reward and neuroprotection [ 92 ].…”

Section: Discussionmentioning

confidence: 99%

Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism

Bove,

Palmieri,

Santoro

et al. 2024

Transl Psychiatry

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Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.

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Implication of Hippocampal Neurogenesis in Autism Spectrum Disorder: Pathogenesis and Therapeutic Implications

Cited by 15 publications

References 183 publications

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

Dopamine D2R and opioid MOR availability in autism spectrum disorder

Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism

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