Cellular and circuit excitability in rodent models of neurodevelopmental disorders

Abstract

Autism spectrum disorders and intellectual disabilities (ASD/ID) are estimated to a↵ect approximately 3-5% of the population. Genetic factors constitute a major risk factor in ASD/ID, accounting for 40 to 50% of cases, with monogenic forms of syndromic ASD representing 5% of cases. Many of the genetic causes of ASD/ID are thought to share common phenotypes at the cellular level, thus animal models of monogenic forms of ASD/ID provide a valuable tool to better understand the underlying pathophysiology of these disorders. In this thesis I examined two rodent models of monogenic forms of ASD/ID associated with developmental delay, impaired cognitive function and epilepsy, namely CDKL5 deficiency disorder (CDD) and Fragile X Syndrome (FXS). First, I examined synaptic function and intrinsic excitability in the hippocampus of a novel Cdkl5 knock-out (Cdkl5-/y) rat model of CDD. I show an increase in long-term potentiation (LTP) in the hippocampus of Cdkl5-/y rats, consistent to what has previously been reported in mouse models of this disorder. I extend this finding by using a combination of electrophysiological and histological techniques to assess the properties of pre-synaptic neurotransmitter release together with multiple post-synaptic mechanisms that may contribute to the observed Cdk-/y phenotype. Intriguingly, I demonstrated that many of the mechanisms that have been postulated to underlie enhanced LTP are not altered in Cdkl5-/y rats when tested at the single cell level, including changes in AMPAR/NMDAR ratios and increased expression of Ca2+-permeable AMPA receptors. Second, I examined the contribution of the axon initial segment (AIS) to the cellular hyperexcitability of CA1 pyramidal cells in the Fmr1-/y mouse model of FXS. I show that increased AIS length in CA1 pyramidal cells in Fmr1-/y mice is associated with cellular hyperexcitability. I show that depolarisation induced AIS plasticity is unaltered in Fmr1-/y mice is associated with cellular hyperexcitability. I show that depolarisation induced AIS plasticity is unaltered in Fmr1-/y mice, despite an observed reduction in synaptic transmission of EC inputs. In the final chapter of this thesis, I built on my findings in the hippocampus of Fmr1-/y mice, despite an observed reduction in synaptic transmission of EC inputs. In the final chapter of this thesis, I built on my findings in the hippocampus of Fmr1-/y mice. I found the AIS developmental trajectory to be a↵ected in a layer specific manner, with Fmr1-/y mice exhibiting a typical developmental profile in L2/3 and 5 but altered AIS development in L4. However, I did not observe an e↵ect of visual deprivation on AIS length or cellular excitability in either genotype. In summary, this thesis provides insights into the cellular excitability and synaptic physiology in two rodent models of monogenic ASD/ID. I further our existing understanding of rodent models of CDD by characterising hippocampal synaptic and intrinsic physiology in a novel rat model of this disorder, highlighting the need for the identification of robust cross species phenotypes that can be used as potential biomarkers and therapeutic targets in CDD. Furthermore, I put forward the notion of AIS regulation as a contributor to the underpinning of cellular excitability in rodent models of FXS. Additionally, this work contributes to the growing body of evidence showing that compensatory mechanisms have a major contribution to the phenotypes observed in rodent models of ASD/ID, and which should be taken into consideration when developing potential treatment strategies.