There's a triplication of chromosome 21 due to nondisjunction. This affects up to 400 genes and many regulatory microRNAs, which causes an overall increase in genes, product, and proteins. There are two, not mutually exclusive, hypotheses:
- **Gene Dosage Effect Hypothesis:**  the disease phenotype is caused by the dosage imbalances on chromosome 21
- **Amplified Developmental Instability Hypothesis:**  dosage imbalances in the hundreds of affected genes cause nonspecific changes in genome-wide expression

Down Syndrome arises from the result of quantitative (i.e. the amount) gene changes.  In additition to these genetic changes,  there are also neuroanatomical  differences, such as:
- Reduced dendritic branching
- Reduced synaptic density 
- Abnormalities in the layers of the cortex (layers II and IV) become apparent after the 22nd week of gestation. There’s a slight increase in dendrites at birth but by around 6 months of age that number decreases
- Decreased GABAergic inhibition in layers II and IV of the cortex - which could explain why some persons with Down Syndrome get seizures
- Altered glutamatergic synapses with larger, though fewers spines


Neurobiology of Down Syndrome

GIRK2 - a G protein-coupled potassium channel that stabilizes resting potential
- Encoded by the *KCNJ6* gene, which is upregulated in Down Syndrome and causes enhanced neuronal inhibition
- This is likely why persons with Down Syndrome have hippocampal-dependent learning impairments


Olig1 and Olig2 - transcription factors
- Regulate neurogenesis of GABAergic interneurons
- Increased expression of these two factors causes an increase in inhibitory neurons


DYRK1A - a dendritic protein
- Associated with GTPase dynamin 
- Involved with synaptic vesicle recycling and membrane trafficking
- Modulates cAMP response element binding protein, which is involved in synaptic plasticity
- Increased expression of *DYRK1A*  gene causes impaired spatial learning by impairing retrieval of synaptic proteins
- Interacts with synaptojanin 1, which is regulated by the Down Syndrome Critical Region gene 1 (*DSCR1*) and is a phosphotase required for synaptic vesicle endocytosis


*DOPEY2*  gene
- Regulates cortical cell density
- The increased amount seen in persons with Down Syndrome likely leads to abnormal cortical layering


*SIM2*  gene
- Transcriptional regulator that controls *shh* (sonic hedgehog) expression, which controls cell growth and differentiation
- Increased expression leads to mild learning impairment and decreased sensitivity to pain


TPRD protein
- Regulates neurite growth 
- Increased expression seen in Down Syndrome inhibits neurite extension, leading to abnormal cortical layering


Amyloid Precursor Protein (*APP*  gene)
- Located on chromosome 21, so triplication in Down Syndrome causes an increase in this gene
- Causes the plaque build-up seen in Alzheimer’s Disease, so the increased amount of *APP*  gene in Down Syndrome is likely why these persons are likely to develop the disease so early in life


SOD1 - a copper-zinc (Cu-Zn) superoxide dismutase, which is an enzyme that’s important for inactivating oxygen free radicals
- Increased expression of this enzyme causes impaired long-term potentiation (LTP) and a decrease in protein clearance through the ubiquitin proteasome system


S100ꞵ - secreted glial calcium binding protein that's often associated with blood vessels 
- Amplified in Down Syndrome and Alzheimer’s Disease
- Increased expression leads to changes in dendritic spine density in the hippocampus and impairments in spatial learning, which suggests that some cognitive symptoms in Down Syndrome are also caused by abnormal glial-neuronal interactions


Genes Affected by the Triplication of Chromosome 21 and Their Links to Down Syndrome Symptoms

This animal model is achieved by making changes to chromosome 16 in mice, which affects 150 genes. These genetically modified mice have similar symptoms to those seen in persons with Down Syndrome:
- Smaller in size
- Craniofacial abnormalities
- Impairments in hippocampal-dependent long-term memory tasks
- Decreased number of neurons
- Decreased complexity in dendritic branching


There are also similar neuroanatomical differences to those seen in humans, like:
- Decreased excitatory input
- Altered placement of GABAergic inhibitory synapses, which innervate the base of the dendritic spine and therefore have a much larger effect on the hippocampus
- Increased long-term depression (LTD)



Mouse Model of Down Syndrome: *Ts65Dn* 

Studies are currently being done into possible treatments for both symptoms and the overall genetic defects of Down Syndrome, though nothing has currently been approved in humans. One such treatment involves restoring the correct number of the Olig1 transcription factor. Doing this helps the hippocampus express the correct number of inhibitory interneurons and this essentially permanently corrects all cognitive symptoms seen in Down Syndrome, which suggests that the cognitive phenotype in Down Syndrome may actually be reversible. In *Ts65Dn*  mice, memory function was correct using GABAa receptor inhibitors (picrotoxin, bilobalide, and pentylenetetrazole). This still needs to be fully tested in humans, and one such study is being carried out. GABA-A receptor blocker RG1662 has been shown to be safe in a phase I study and is now being studied in a multiclinic study.


Emerging Treatments for Down Syndrome

The science, research, and biological evaluation of Down syndrome allow us to understand it as we can today. Ways in which scientists have made progress in Down syndrome studies can be appreciated through
- the neurobiology of Down syndrome
- Genes affected by the triplication of chromosome 21 and their links to Down syndrome symptoms
- Mouse Model of Down syndrome: Ts65Dn
- Emerging treatments of Down syndrome


University of Virginia, Charlottesville

Down syndrome is a developmental disorder that causes varying degrees of physical and cognitive disability. It is the most common genetic condition and is caused by a chromosomal abnormality in which there is an extra copy of chromosome 21. 

Down Syndrome

As a result of atypical chromosomal composition, the characteristics of individuals with Down syndrome present in many aspects of their development, both physical and cognitive. Individuals with Down syndrome are characterized by…
 - Physical characteristics of Down syndrome
 - Cognitive characteristics of Down syndrome
- Developmental characteristics of Down syndrome
- Comorbidities of Down syndrome


Characteristics of Down syndrome

The Science of Down syndrome

Down syndrome is caused by the presence of an extra copy of the 23rd chromosome, resulting in an excessive number of chromosomes: 47, as opposed to 46. However, variations of this chromosomal abnormality exist. And though it is the most common chromosomal abnormality, births with Down syndrome are random and not linked to any health or socioeconomic patterns. We can best explore the variations of the occurrence of Down syndrome through:  
- Types of Down syndrome
- Trisomy 21
- Frequency 
- Inheritance 
- Factors that increase risk 

What causes Down syndrome?

Individuals with disabilities and their families and caretakers often identify with the umbrella term of the “Down syndrome community.” To understand this disability, it is important to understand the cultural and social characteristics of the community. We can understand the community by considering how the Down syndrome community prefers to be communicated with, the employment and education trends, disparities in outcomes, how individuals with Down syndrome see themselves and each other, and the experiences of caretakers. 

Culture of Down syndrome

The life expectancy for people with down syndrome has increased from 10 years of age in 1960 to 47 in 2007. It is still lower than people without it because of the additional health conditions and lower birth weight associated with this syndrome. Race has also been seen to impact how long one can live with this condition. One explanation for this increase in life expectancy is that people have stopped institutionalizing those with down syndrome.

Life expectancy for people with Down Syndrome

Such factors may include:
- chemotherapy;
- cigarette smoking;
- chemicals that disrupt hormone-releasing glands;
- hormones the person receives through treatment for example.

Environmental factors that can influence probability of Down Syndrome

Dementia is common in adults with Down Syndrome, but it is difficult to receive this diagnosis. It may be manifested in different ways depending on the individual. 

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