The prevalence of intellectual disabilities is often quoted at 1 %. A meta-analysis of articles published between 1980 and 2009 confirmed this prevalence. Changes in diagnostic practices, population characteristics, and exposure to known risk factors in recent years place this estimate in question and make it imperative to examine more recent studies of prevalence and incidence. Twenty relevant articles were obtained from five databases (PubMed, Embase, PsycInfo, Cochrane, and MEDLINE), published between 2010 and 2015. Most studies (n = 17) only reported prevalence estimates, while two provided incidence estimates. Various methodologies were applied, with the majority of studies (n = 16) using administrative data. Heterogeneity in study settings, methodologies, age groups, and case definitions contributed to a range of prevalence estimates (0.05 to 1.55 %). Future research should include reproducible and consistent definitions of intellectual disabilities, provide age-specific estimates, and monitor changes in prevalence over time.

An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009). For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+) and chloride channels (Vella et al., 2015). This astroglial swelling may be overwhelmed, under ischemic conditions, due to the increased levels of glutamate and extracellular K+ (Lai et al., 2014; Vella et al., 2015). The increase in extracellular K+ contributes to neuronal damage and loss through the initiation of harmful secondary cascades (Nwaobi et al., 2016). Reducing the amount of extracellular K+ could, in theory, limit or prevent neuronal damage and loss resulting in an improved prognosis for individuals following ischemic stroke. Kir4.1, an inwardly rectifying K+ channel, has demonstrated an ability to regulate the rapid reuptake of this ion to return the cell to basal levels allowing it to fire again in rapid transmission (Sibille et al., 2015). Despite growing interest in this area, the underlying mechanism suggesting that neuroprotection could occur through modification of the Kir4.1 channel's activity has yet to be described. The purpose of this review is to examine the current literature and propose potential underlying mechanisms involving Kir4.1, specially the mammalian target of rapamycin (mTOR) and/or autophagic pathways, in the pathogenesis of ischemic stroke. The hope is that this review will instigate further investigation of Kir4.1 as a modulator of stroke pathology.

Stroke is one of the leading causes of death and disability in Canada. Despite increasing morbidity rates, current stroke treatments are ineffective outside of a three-to six-hour window following symptom onset, indicating a critical need for alternative approaches to the management of symptoms. One such alternative is the use of antidepressant therapy to treat post-stroke depression (PSD). A pilot survey conducted for this dissertation found that Canadian hospitals and stroke centers frequently prescribe antidepressants following strokes. This survey also demonstrated that antidepressant treatment improved respondents, experience in two outcome domains (depression and anxiety or mood swings) and may have an impact on further deterioration in two specific domains (pain or numbness and inattention to one side of the body). The two antidepressants commonly used to treat PSD, fluoxetine and nortriptyline, have previously been shown to inhibit an inward rectifying potassium channel, known as kir4.1. Following a stroke, the kir4.1 channel has been shown to be responsible for the rapid reuptake of potassium to return the cell to baseline levels. This dissertation sought to examine the impact of inhibiting kir4.1 channel activity, using two common antidepressants (fluoxetine and nortriptyline), on proteins involved in astrocytic inflammation and cell survival post-stroke. The developmental expression pattern was first characterized as many developmental factors are known to play an important role in plasticity following traumatic brain injuries. The expression pattern of IL-1β, kir4.1, p38, and pERK1/2 following stroke were also evaluated; these four proteins were also examined following treatment with antidepressants (fluoxetine or nortriptyline).Four major conclusions were drawn from the animal studies. First, the level of kir4.1 expression fluctuated with development, with higher expression observed at E18 and P7 compared to older timepoints, and at P21 compared to aged adults. Second, significant cell death was seen iii at the 24-hour and three-day timepoints, followed by substantial cellular recovery by day seven post-stroke. Thirdly, an increase in IL-1β was found to coincide with reduced expression of the kir4.1, p38β and pERK1/2 expression in the first six hours after stroke. Only pERK1/2 remained reduced after six hours. Finally, nortriptyline was found to significantly increase kir4.1 and pERK1/2 expression, and significantly decrease p38β expression, when compared to the fluoxetine and saline conditions. Findings from the animal studies provide support for the idea that tricyclic antidepressants may be more appropriate in the preventative treatment of post-stroke depression (PSD). The clinical significance of these relationships remains unknown; however, both antidepressants appear to be prescribed to individuals who have recently suffered a stroke. Furthermore, it is likely that the kir4.1 channel is involved in the astrocytic response to antidepressants treatment in the prevention of PSD. iv Acknowledgement...