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Application of In Vivo Ca2+ Imaging in the Pathological Study of Autism Spectrum Disorders
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Two-photon microscopy is a useful technique to study the circuit level mechanism of neurological disorders, such as autism spectrum disorders (ASDs). For example, GCaMP6s was expressed in the primary visual cortical excitatory pyramidal cells and inhibitory parvalbumin (PV)-expressing interneurons, respectively, in a mouse model of Fragile X syndrome, one of the ASD mouse models (Nakai et al., 2001). These neurons’ response to orientation visual stimulation is characterized in detail via in vivo two-photon Ca2+ imaging. This study showed that the percentage of orientation-selective pyramidal cells decreases in Fragile X syndrome mice and the visually evoked activity is reduced in their PV neurons, leading to orientation-tuning deficits. Another group recorded whisker touch-related activity of excitatory and inhibitory neuronal populations in layer 2/3 of the somatosensory cortex by two-photon calcium imaging (Michaelson et al., 2018). They found reduced sensory responses in both excitatory and inhibitory neurons in mice with SYNGAP1 mutation, another ASD mouse model. Their findings suggest that SYNGAP1 mutation disrupts sensory processing within the somatosensory cortical circuits. Two-photon imaging is also used in ex vivo study with hippocampal slices of ASD mouse models with mutations in methyl-CpG-binding protein 2 (MECP2) (Lu et al., 2016). This study covers three mouse models of MECP2 disorders: constitutive Mecp2 null, mosaic Mecp2+/−, and MECP2 duplication mice. It discovers that the hippocampal circuits in these three lines of mice share three novel signs of hippocampal circuit dysfunction. First, the hippocampal CA1 pyramidal neurons tended strongly to fire in synchrony. Second, the circuit was not able to restore homeostasis after perturbations of excitatory-inhibitory balance. Third, the inhibitory neurons showed abnormally low excitatory synaptic responses. Thus, even in the context of very different transcriptional effects, the effect at the circuit level can be shared—perhaps not just between Rett and MECP2 duplication syndrome, but among other intellectual disability disorders.
Gene therapy for neurological disorders: challenges and recent advancements
Published in Journal of Drug Targeting, 2020
Stefanie A. Pena, Rahul Iyengar, Rebecca S. Eshraghi, Nicole Bencie, Jeenu Mittal, Abdulrahman Aljohani, Rahul Mittal, Adrien A. Eshraghi
ASD can be divided into monogenic and polygenic ASD, depending on the number of gene variants. Monogenic ASD conditions usually account for only 5% of ASD cases and include autism as part of a syndrome, such as Fragile X syndrome, Rett Syndrome, MECP2 duplication syndrome, Tuberous sclerosis and Angelman syndrome [106,107]. In ASD disorders defined by loss of function mutations include Rett Syndrome, Fragile X Syndrome and Tuberous sclerosis. In the arena of autism, monogenic forms of ASD have been investigated to see if gene therapy can be used. Rett syndrome (RTT) is an x-linked neurodevelopmental disorder primarily caused by the loss of Mecp2. A self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AVV9-MCO) was delivered to the Mecp2-deficient (KO) mice. It was found that the AAV9-MCO administered viral genome (vg)/mouse was able to significantly increase survival and weight gain and delay the occurrence of behavioural deficits [106].
Understanding and managing respiratory infections in children and young adults with neurological impairment
Published in Expert Review of Respiratory Medicine, 2023
Marijke Proesmans, Francois Vermeulen, Mieke Boon
In the assessment and treatment of children with NI and respiratory problems we should not forget to assess comorbidities. Control of epilepsy, treatment of malnutrition are all important aspects. We tend to forget that children with NI may have common diseases like asthma, allergy, or immunodeficiency. Specific syndromes or genetic diseases may come with known comorbidities. For example, MECP2 duplication syndrome is associated with immunodeficiency [62], and 22q11 deletion with T-cell-related immunodeficiencies [63,64] and trachea-bronchomalacia [65].