Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.
Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration.
VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, USA; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Devsmita
D
Das
Department of Physical Therapy, P.O. Box 910, Arkansas State University, State University, AR, USA.
Cristy
C
Phillips
VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, USA.
Wayne
W
Hsieh
VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, USA.
Krithika
K
Sumanth
VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, USA; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Van
V
Dang
VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, USA; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA. Electronic address: asalehi@stanford.edu.
Ahmad
A
Salehi
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D004314:Down Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*
D018377:Neurotransmitter Agents
Alzheimer's disease; Down syndrome; Formoterol; Locus coeruleus; l-Dops