The role of chromatin remodelling factors in cerebellar development and autism
Tez Türü: Yüksek Lisans
Tezin Yürütüldüğü Kurum: University of London-Kings College London, Social, Genetic & Developmental Psychiatry Centre, İngiltere
Tez Danışmanı: Albert Basson; Cathy Fernandes
Tezin Onay Tarihi: 2015
Tezin Dili: İngilizce
Desteklendiği Program: Diğer
Özet:
ABSTRACT
Autism is a complex neurodevelopmental disorder with recognizable symptoms
in early childhood, identified by three fundamental behavioural symptoms: persistent
impairment social interaction, communication and restricted interest and repetitive
behaviours. One percent of the population around the world is influenced by autism.
Autism is associated with various rare genetic and medical conditions. CHARGE
syndrome is one of the disorders under this umbrella term. Children with CHARGE
syndrome and those with autism have overlapping behavioural traits, neuroanatomical
defects, and genetic factors. One of the most implicated genes associated with
CHARGE syndrome is CHD7 encoding the ATP-dependent chromatin remodeler.
CHD7 gene is involved in development of cerebellum, which is consistently reported
to be associated with neuroanatomical defects in individuals with autism. The
mechanisms underlying deficits in the syndrome associated with the autistic features
remain unidentified. Given the genomic, brain anatomy, pharmacological treatment
response similarities between mice and human, animal models of psychiatric disorders
emerged as tools to elucidate the exact role of genes and their effects over time by
creating mutant phenotypes resembling human disease phenotypes. An investigation
of the behavioural effects of the conditional Chd7 deletion in mice was performed to
gain a better understanding of its role in ASD. Wildtype, knockout Chd7 male and
female mice were tested for impairments in short-term memory (novel object
discrimination task), spatial learning, reference memory and/or cognitive flexibility
(Morris water maze task) (n = 12 per genotype, per sex). Alternative cognitive task for
the assessment of short-term memory (spontaneous spatial novelty discrimination in
a Y maze) was piloted in C57BL/6J mice to assess its utility for future behavioural work
(n = 12, male). Cerebellar hypoplasia in Chd7 conditional knockout mice is associated
with mild motor deficits. This study has several limitations that affect robustness in
assessments of cognitive abilities in mice regarding few numbers of cognitive tests
and evaluation of the mutant line. Although this work reports no strong behavioural
deficiencies associated with cerebellar hypoplasia, these observations are still be of
significant interest in elucidating isolated cerebellar hypoplasia because it is one of the
main factors influencing autistic phenotypes associated with Chd7 deficiency.