Our understanding of inheritance of genes goes all the way back to 1866. Gregor Mendel was the first scientist to study and popularize the concept of recessive and dominant alleles in genetic inheritance. Although the mechanisms have been studied for many years, our understandings of the genetic contributing factors of Down syndrome are incomplete. However, an extra copy of chromosome 21 is thought to be the most common cause of Down syndrome. This results from meiosis incorrectly partitioning chromosome 21 during gamete formation. Meiotic nondisjunction type I and type II both result in abnormal gametes that are either missing a chromosome, or possess an extra one – this is known as aneuploidy.
As a result, both the fertilization of an abnormal egg cell by a normal sperm cell or the fertilization of a normal egg cell by an abnormal sperm cell can occur. Unfortunately, a fertilized egg that is missing a chromosome for any of the autosomes will be spontaneously aborted early in embryonic development. However, an aneuploidy that occurs in the X chromosome is viable, and will develop into an individual with Turner’s syndrome. An aneuploidy that results from an extra copy of a chromosome is labeled a trisomy. Trisomy of the X chromosome is commonly experienced in aneuploidy. In women, trisomy of the X chromosome results in what is known as triple X syndrome, while in males this results in Klinefelter syndrome. However, a variety of aneuploidy in sex chromosomes does exist, often affecting cognitive abilities, physical appearance, and fertility. Interestingly these aneuploidies are less detrimental to the health of individuals affected than those with extra autosomal chromosomes. Scientists believe this to be due to the inactivation of all but one X chromosome copy and the relatively few number of genes located on Y chromosomes. Trisomies of the autosomes are rare and only survive to term in a handful of fetuses. Chromosomes 8, 9, 13, 18, 21, and 22 are the only autosomal trisomies that have been known to survive, even so, trisomies of 8, 9, and 22 are only viable in the cases that experience mosaicism.
Mosaicism occurs when a mixture of both normal and abnormal cells in the body are found. Again, these aneuploidies are much less likely to survive to term, even then causing a variety of very severe deficits in the individual. For example, Patau syndrome occurs from trisomy in chromosome 13, causing heart defects, neurological deficits, as well as skeletal deformities. This syndrome is one of the rarest occurring in about 1 in every 16,000 infants, with only 20 percent surviving past their first year. Contrastingly, the most common aneuploidy to survive is Trisomy in chromosome 21, having the prevalence of 1 in 700 births. Trisomy 21 is known as Down syndrome. However, production of aneuploidies is not always necessary for the occurrence of Down syndrome. On average, most children either inherit an extra chromosome 21 or are simply born with an extra copy of the chromosome (Eckdahl, 2017). Babies with Down syndrome are usually easily identified soon after birth. However, for a definitive diagnosis, the chromosomes in the blood cells must be analyzed. Symptoms of Down syndrome include a variety of physical abnormalities, some of the most common including hypotension, flattened facial profile, small head, ears and mouth, upward slanting eyes, Brushfield spots on the iris of the eye, and a deep crease across the palm of the hand. Physical development in these individuals is often slower than that of typical children.
However, children with Down syndrome can learn to participate in physical activities similar to other typically developing children. Additionally, children with trisomy 21 are at an increased risk for other certain health problems. For example, nearly half of babies born with Down syndrome will also have Congenital Heart Disease, which can lead to high blood pressure and an inability of the heart to pump and circulate blood efficiently throughout the body. They are also prone to infections due to the disorder causing issues with their immune system. Infants with the disorder have a 62-fold increase in rate of pneumonia, as compared to infants without the disease. They are much more likely to die from untreated infections. Other associations include increase risk of hypothyroidism, blood disorders, sleep disorders, epilepsy, Celiac disease, as well as serious mental and emotional problems. However, not every child will show all the characteristics and signs associated with the disorder, some may exhibit only a few. It is vital to remember that none of the symptoms associated with Trisomy 21 are unique. The common population also often suffers from these issues. Advances in treatment and access to medical has increased the average life expectancy to 60-65 years for individuals with Down syndrome. However, individuals with Down syndrome also exhibit a greatly increased risk of developing early-onset Alzheimer’s Disease (NIH, 2017).
Today, intellectual disabilities are the most common developmental disability. This term, “intellectually impaired,” refers to a condition in which a person has certain limitations on their cognitive functioning. Nearly 6.5 million people in the United States have an intellectual disability. Within this population, Down syndrome is the most commonly identified cause of the impairment. The disorder accounts for nearly 30% of the intellectually impaired population (Rachidi, 2010). However, a child’s level of impairment can range from mild, moderate, to severe. Those with mild deficits are likely able to continue in mainstream education, while others with moderate to severe impairment will likely require additional services to learn basic life skills. Intellectual disability in DS is characterized in many ways, including cognitive delays, language difficulty, learning and memory impairments, problems in changing tasks, as well as other cognitive impairments (Rachidi, 2010). In all likelihood, these children will be able to learn many skills, however, they will most often fall behind the normal developmental markers. Some of the most common difficulties children with intellectual disability face include the cognitive functions of recognizing consequences, solving problems, thinking logically, reasoning, planning, abstract thought, and experiential learning (NDSS, 2018). To measure these abilities, IQ testing is implemented. Individuals with Down syndrome have an IQ of about 50, while typically developing individuals possess an IQ of 90-109 on average (Weiss, 2006). IQ in these individuals begins to decline after the first year of life and continues throughout adolescence and adulthood (Rachidi, 2010). With an IQ significantly lower than average, individuals with DS will likely struggle their entire lives and be unable to partake in many activities of typically developing persons. Several studies have indicated an impairment in working memory in individuals with DS.
Meaning, these individuals perform significantly worse on the active manipulation of information (Lanfranchi, 2010). Evidence suggests that they are more susceptible to interference than typically developing persons, struggling to inhibit predominant but inappropriate responses. Borella et. al tested this using a Stroop task in which individuals with DS were less able to prevent automatic responses. Additionally, they found that these individuals were impaired in their ability to suppress irrelevant information in order to maintain their working memory capacity (2013). Due to the existence of a limit of information that can be stored in the working memory of all individuals, this inability to ignore non-pertinent information can possibly explain why a negative fallout exists in the working memory of individuals with DS. These intellectual impairments observed are considered to be caused by the neurological physical alterations that accompany the disorder from birth in the key regions of learning and memory in the DS brain. Overall, a reduction of brain volume as compared to typically developing individuals is reported. Notably, significant reduction in volume found in the hippocampus, cerebellum, and prefrontal cortex of the brain have been seen in neuroimaging studies (Pinter, 2001). This impairment of the prefrontal cortex could possibly be the cause behind the observed deficits in working memory of these individuals that have been consistently reported. However, deficits in spatial, long-term, and short-term memory are observed in these individuals providing behavioral evidence for hippocampal dysfunction Rachidi, 2010). Down syndrome mice models allow for the investigation of the molecular mechanisms as well as early phenotypic abnormalities found in the disorder. Mouse genes on chromosome 16 are syntenic to those found on human chromosome 21. Trisomy of this mouse chromosome imitates the molecular and clinical phenotypes found in human trisomy 21. These mice exhibit similar neurological alterations and cognitive impairments as associated with Down syndrome.
Although several methods have been experimented with creating partial or total chromosome 16 trisomy in mice, perhaps the most viable and similar to human Down syndrome is the mouse line of Tc1. These mice have been manipulated to generate an aneuploidy mouse line that reliably produces an almost complete human chromosome 21. These mice have successfully been able to model phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, and heart abnormalities found in human DS (O’Doherty, 2007). This method of modeling aneuploidies will also likely prove helpful in the future to modeling other human chromosome aneuploidy syndromes. One study used Ts65Dn mouse models to replicate the effects of Down syndrome. They found significant alterations in the density and morphology of dendritic spines in the mouse models, most notably in the hippocampus. In the fascia dentata of the hippocampus enlarged spines were 10 times as frequent in the Ts65Dn mice as compared to typically developing mice. Mice models for Down syndrome have exhibited changes in induction of long-term potentiation, density and size of dendrites, and structure of synapse in addition to cognitive deficits. Behavioral tests in these mice have showcased these impairments. In tests like the open-field test, novel recognition test, and T-maze test they were shown to perform significantly worse than controls. Previous studies had supported deficits in LTP induced by high-frequency stimulation of the CA1 region of the hippocampus.
However, Costa and Gybko (2005) found LTP to be induced in the CA1 in both HFS and theta burst stimulation. Their results showed no difference in HFS induced LTP, but only in TBS induced LTP of the CA1 region. A significant reduction of the amount of TBS-induced LTP in the Ts65Dn mice was observed compared to typically developing mice. However, this specific LTP deficit was rescued by the addition of Picrotoxin, a GABAA antagonist. This lead researchers to uphold the hypothesis of an increase in GABAA – mediated inhibition or in the plasticity of the inhibitory circuitry of Ts65Dn mice possibly underlying the synaptic plasticity deficits in DS models (Costa, 2005). GABAA receptors consist of five subunits that surround a central chloride-ion selective channel gated by GABA, GABA standing for gamma-aminobutyric acid. GABAA receptors are the main inhibitory neurotransmitter receptors in the brain of mammals (Sigel, 2012). Presynaptic GABAA receptors occur at hippocampal mossy fiber synapses. An endogenous neurosteroid selective for high-affinity δ-subunit-containing GABAA was applied and resulted in the depolarization of mossy fiber synaptic terminals. Once depolarization had occurred, action-potential dependent Ca2+ influx was enhanced, thus further facilitating excitatory glutamatergic transmission in pyramidal neurons of the hippocampus.
Blocking of the GABAA receptors, however, depolarizes the mossy fiber terminals. This results in an increase in input resistance, a decrease in excitatory postsynaptic potential width, and diminishes action potential-dependent Ca2+ influx. Interestingly, this has led scientists believe this indicates that a subset of presynaptic GABA receptors is tonically active, meaning activity is present even in the absence of stimulation. Enhanced Ca2+ influx that occurs as a result of GABAA receptor stimulation is thought to be the driving force behind GABAA receptor induced LTP in the mossy fibers. Due to postsynaptic depolarization playing little role to no role in mossy fiber LTP induction, experimental results have implied GABAA receptors hold an important role in the synaptic plasticity of glutamatergic synapses, modeling the effects reported for kainate receptors (Ruiz, 2010). Thus presynaptic GABAA receptors actually have an excitatory role in the induction of LTP. Genes present in the critical region of Down syndrome on chromosome 21 often result in their overexpression. Regulator of Calcineurin 1 (RCAN1) which interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways is found on this critical region. RCAN1 overexpression in neurons has been shown to impair synaptic plasticity, neurotransmitter release, and on a larger scale, learning and memory. Cells of trisomy 16 mouse models were observed to express levels of Rcan1 1.8-fold higher than control cells using Western blot assays. Rcan1 overexpression was then knocked down to a similar level to that of controls, thus restoring Ca2+ -dependent exocytosis (Vásquez-Navarrete, 2018). Brain tissue taken from the autopsy of individuals with Down syndrome indicated significantly reduced levels of noradrenaline, dopamine, serotonin, and choline acetyltransferase in both cortical and subcortical regions of the tissue. This tissue also displayed neuritic plaques and neurofibrillary tangles, indicating neuropathological abnormalities similar to that of Alzheimer’s Disease (Godridge, 1987). Down syndrome may hold the key to understanding the pathogenesis and progression of Alzheimer’s Disease. The studying of young patients with DS may help to expose the pathological alterations and abnormalities that predispose an individual to development of AD. The formation and distribution of senile plaques and neurofibrillary tangles in middle-aged individuals with DS are qualitatively the same as those of the same age with Alzheimer’s Disease. By the age of 40 amyloid plaques and neurofibrillary tangles are a common characteristic of the DS brain.
Furthermore, approximately two thirds of individuals with DS will develop dementia by the age of 60 (Wiseman, 2015). Interestingly, a transitional period in DS individuals from between 20 and 40 years of age seems to exist, during which there is an observed complete absence of senile plaques and neurofibrillary tangles. However, after the age of 40 the presence of senile plaques and neurofibrillary tangles is seen in almost all DS individuals, with only 3 patients in over 40 years have been reported to not show these atrophies (Mann, 1987). This greatly increased risk of early-onset Alzheimer’s disease is thought to be brought about by the presence of three copies of the amyloid precursor protein. This additional copy may drive the development of AD in DS individuals by increasing the levels of amyloid-beta protein, a cleavage product of APP that misfolds and accumulates in the brain in the pathology of AD. Duplication of APP, a rare genetically inherited trait, causes the development of small internal chromosome 21 duplications. These duplications also lead to the development to early-onset Alzheimer’s Disease. In reciprocal, the partial trisomy of chromosome 21 does not lead to the extra presence of APP and does not lead to AD (Wiseman, 2015). Although, a lot of help is available to individuals with Down syndrome, there remains no viable treatment for its associated intellectual impairments. However, in the Ts65D mouse model for DS, a drug called memantine has been shown to produce significant improvements in learning abilities.
However, mematine’s biological mechanism is still poorly understood. LTP in the CA1 region of the hippocampus produced by theta-burst stimulation has been shown to be significantly reduced in the Ts65D mouse model for DS. Addition of drug memantine was shown to rescue the learning and memory deficits previously seen in TBS. Scott-McKean et. al (2018), however, observed depression in both E-LTP and L-LTP induced by HFS as compared to controls. The addition of memantine in this case made no significant effects on the HFS LTP in the Ts65D mouse model. At a therapeutic level, memantine is not seen to have any adverse effects on either induction or maintenance of LTP in the hippocampus. Picrotoxin was once again added to determine its viability as a potential therapeutic for DS. Although the drug did increase the mean levels of L-LTP in Ts65D derived slices to a similar level as controls, it also produced seizure-like oscillations in postsynaptic potentials. This is likely due to over-stimulation of GABAergic synapses. Therefore, picrotoxin is not likely to be of any therapeutic value. Amyloid-beta oligomers and rPrP were also found to have little to no effect on HFS E-LTP (Scott-McKean, 2018). Research into the mechanisms of Down syndrome will continue for many more years. The effort to answer all of the unknown questions of the disorder will be a multidisciplinary effort, synthesizing work from a vast number of fields in the sciences. Making discoveries in this area of research, however, is very useful. As the number one cause of intellectual disability in the United States, there are many who will benefit from any knowledge that is uncovered on the disorder. Additionally, Down syndrome has the potential to serve as extremely useful and viable working model for Alzheimer’s disease. Thus, future resource on the disorder will not only benefit those with Down syndrome but also those suffering from the devastating disease of Alzheimer’s.
