Monogenic mutations in synaptic proteins are known to cause severe and low functioning cases of autism spectrum disorder and intellectual disability (ASD/ID) (Wright et al., 2018). One of the most prevalent monogenic causes of moderate to severe non-syndromic and syndromic ID with a high co-morbidity of seizures and altered sensory processing is SYNGAP1 haploinsufficiency (Hamdan et al., 2009; Hoischen et al., 2014). Resulting from de novo truncating or frameshift mutations in the SYNGAP1 gene on human chromosome 6, SYNGAP1 haploinsufficiency leads to a 50% reduction of the encoded synaptic GTP-ase activating protein (SynGAP) (Hamdan et al., 2009). Pre-clinical models of Syngap1 haploinsufficiency have provided an invaluable tool to understand the underlying pathophysiology resulting from a reduction of SynGAP. The heterozygous mouse model of Syngap1 haploinsufficiency (Syngap1+/-) demonstrates a range of cellular, physiological and behavioural abnormalities from early development to adulthood (Chen et al., 1998; Kim et al., 1998; Komiyama et al., 2002; Rumbaugh et al., 2006; Muhia et al., 2010). Key among these phenotypes is brain region and cell-type specific hyper- and hypo-excitability, causing an excitation/inhibition imbalance which manifests as disrupted circuit function (Clement et al., 2012, 2013; Ozkan et al., 2014; Aceti et al., 2015; Berryer et al., 2016; Katsanevaki, 2017). Neuronal excitability is defined as the probability of action potential (AP) generation in response to a given current. The site of AP generation is a specialised cellular compartment located between the somatodendritic and axonal compartments of a neuron, called the axon initial segment (AIS). The AIS is a dynamic structure, shown to alter its length and position along the axon in response to altered physiological and pathological conditions (for review see Rasband (2010)). Prolonged increase in neuronal activity causes shortening and a distal shift of the AIS (Evans et al., 2015; Grubb and Burrone, 2010) while extended periods of decreased neuronal activity result in lengthening and proximal shift of the AIS (Kuba et al., 2006; Kuba, 2012). The functional consequence of this morphological plasticity is altered intrinsic excitability such that neurons with distally located, shorter AISs exhibit increased AP threshold with subsequent production of fewer APs in response to a given current while neurons with longer, proximal AISs exhibit decreased AP threshold and increased frequency of AP firing (Kuba et al., 2006; Grubb and Burrone, 2010; Kuba et al., 2010; Kuba, 2012; Evans et al., 2015). Given this ability of the AIS to alter cellular excitability and the evidence of altered excitability in pre-clinical models of SYNGAP1 haploinsufficiency, this thesis tests the hypothesis that alterations in AIS length will underlie some the altered cellular excitability observed upon reduction of SynGAP. In order to test this hypothesis, first a characterisation and comparison of AIS lengths between Syngap1+/- and control juvenile rats was undertaken across six brain regions previously known to exhibit altered cellular excitability or be involved in behaviours that are altered in Syngap1 haploinsufficiency. These brain regions include the prelimbic medial prefrontal cortex (mPFC-PL), somatosensory cortex - barrel fields (S1BF), Cornu Ammonis 1 and 3 (CA1, CA3) sub-fields of the dorsal hippocampus, the lateral (LA) and basal (BA) nuclei of the amygdala and the primary visual cortex 1 (V1). Juvenile animals were chosen to reflect the developmental underpinnings of this disorder as Syngap1+/- mice exhibit alterations in synaptic physiology at this age (Barnes et al., 2015) and it coincides with the developmental critical period for some of the brain regions analysed, including the V1 and BLA. Further, the AIS has been shown undergo developmentally regulated alternations in its morphology during this time-period. Statistical analysis of results and post-hoc interactions of brain-region and genotype were analysed using a linear mixed modelling (LMM) approach to account for the non-normal distribution of the data-sets. Subsequently, the effects of Syngap1 haploinsufficiency on morphological plasticity of the AIS was tested. This included analysis and comparison of genotype specific changes in AIS lengths over development and following a cued fear conditioning associative-learning paradigm. Lastly, as cell-type specific differences in cellular excitability have been noted in the Syngap1+/- mouse, AIS lengths were compared across genotypes in cells of the mPFC and BLA with specific projection targets. In addition to studying the difference of AIS length in rat models of SYNGAP1 haploinsufficiency, a similar study was undertaken in this thesis in rat models of Fragile-X syndrome, Cowden's syndrome, NLGN3-associated non-syndromic ID, NRXN1 and CNTNAP2 associated ASD/ID. This work was undertaken to study the hypothesis that diverse genetic causes of ASD/ID converge onto common cellular pathways, and, as preclinical models of these disorders all exhibit evidence of altered cellular excitability, alterations in AIS length might underlie some of these changes. The work documented in this thesis provides the first characterisation of AIS lengths across pre-clinical models of Syngap1 haploinsufficiency as well as across multiple monogenic rat models of ASD/ID. The results indicate that in almost all the brain-regions and models studied, AIS morphology remained unaltered between heterozygous/homozygous animals and their wild-type littermate controls, causing a rejection of the hypothesis that alterations in AIS morphology is a common cellular pathway underlying changes in cellular excitability across these models. However, provided here is the first evidence of AIS morphology in the mPFC-PL being differentially altered in Syngap1 haploinsufficiency compared to control animals when subjected to a cued fear conditioning paradigm as well as alterations in AIS morphology in the mPFC, S1 and BA in a rat model of Fragile-X syndrome.