The establishment of dendrite morphology is crucial for normal neuronal communication in the brain. This development includes both the spatial and functional assembly of signal transduction machinery at synaptic sites and precise patterning of dendrites and their branches. Dendrite branching plays an important role in normal brain function. Branching patterns, the relationship between the primary dendrites arising from the cell body and the secondary dendrites arising from primary dendrites, appear to be cell-type specific and play a role in determining how information is received and processed by a neuron. Further, trafficking of proteins during neuronal development and homeostasis affects or is related to dendrite branching. The amount of branches that a dendrite, or input center of a neuron, contains is thought to be directly related to learning and memory. In many learning disorders, such as autism, Rett syndrome, Down syndrome, Fetal Alcohol syndrome and Alzheimer's disease, patients show a reduced number of dendrite branches. These patients also often show alterations in the metabolism, or breakdown, of a class of compounds called purines.
Clues to how neurons regulate their dendritic morphology come from studies of patients with disorders that result in cognitive deficits. Evidence suggests that patients with these disorders have defects in dendrite number and arborization, as well as deficits in purine production, purine metabolism, or pterins, which are important for purine synthesis. Although these studies are mostly correlative, the first evidence for the idea that purine metabolic disorders underlie cognitive defects was from patients with Lesch-Nyhan syndrome (LNS). LNS is an X-linked disorder that involves the absence of hypoxanthine guanine phosphoribosyltransferase (HPRT) (Lesch and Nyhan, Am. J. Med. 36:561-70 (1964); Seegmiller et al., Science 770:1682-4 (1967); Rossiter and Caskey, Drugs Aging 2:117 (1995)). LNS patients suffer from movement disorders, self-injury, and mental retardation. This deficit always results in increased uric acid levels in the urine, reflecting alterations in purine metabolism, and patients often have neurological abnormalities. Besides Lesch-Nyhan syndrome, both dendrite number or branching defects and purine synthesis/metabolism defects are seen in individuals with autism, (Jaeken and Van den Berghe, Lancet 2:1058 (1984); Stone et al., Nat. Genet. 1:59 (1992); Raymond et al., Acta. Neropathol. 91:117 (1996); Page and Coleman, Adv. Exp. Med. Biol. 431:793 (1998); Page and Coleman, Biochim. Biophys. Acta. 1500:291 (2000); Herbert et al., Brain 126:1182 (2003)); Rett syndrome (Belichenko et al., Neuroreport. 5:1509 (1994); Belichenko and Dahlstrom, J. Neurosci. Methods 57:55 (1995); Rocchigiani et al., Neuropediatrics 26:288-92 (1995); Boltshauser et al., Am. J. Med. Genet. Suppl. 1:317-21 (1986); Zoghbi et al., Ann. Neurol. 25:56 (1989); Subramaniam et al., Neurology 48:399 (1997); Messahel et al., Eur. J. Paediatr. Neurol. 4:211 (2000); Armstrong, Brain Dev. 23 Suppl 1:S72. (2001); Raemaekers et al., J. Cell Biol. 162:1017-29 (2003)); Down's syndrome (Fuller et al., Science 137:868 (1962); Huttenlocher, Neurology 20:381 (1970); Huttenlocher, Neurology 24:203 (1974); Purpura, Science 186:1126 (1974); Purpura, UCLA Forum Med. Sci. 18:141 (1975); Marin-Padilla, J. Comp. Neurol. 167:63 (1976); Takashima et al., 1981 Brain Res. 225:1 (1981); Puukka et al., Clin. Chim. Acta. 126:275 (1982); Puukka et al., Biochem. Med. Metab. Biol. 36:45 (1986); Becker et al., Ann. Neurol. 20:520 (1986); Takashima et al., Brain Dev. 11:131 (1989); Schulz and Scholz, J. Hirnforsch 33:37 (1992); Prinz et al., Histol. Histopathol. 12:895 (1997); James et al., Am. J. Clin. Nutr. 70:495 (1999); Kaufmann and Moser, Cereb. Cortex. 10:981 (2000); Hobbs et al., Am. J. Hum. Genet. 67:623 (2000)) and Fragile-X syndrome (Berry-Kravis and Huttenlocher, Ann. Neurol. 31:22 (1992); Roessler et al., J. Biol. Chem. 268:26476 (1993); Irwin et al., Am. J. Med. Genet. 98:161 (2001); Nimchinsky et al., J. Neurosci. 21:5139 (2001); Galvez et al., Brain Res. 971:83 (2003); Garcia-Pavia et al., Arthritis Rheum. 48:2036 (2003); Lee et al., Development 130:5543 (2003)). There are also reports of decreased dendrite number in patients with Alzheimer's disease (for example Arendt et al., J. Neurosci. 17:516 (1997); Ohm et al., Acta. Neuropathol. (Berl) 103:437 (2002)).
Thus, although there is no current consensus on how the absence of HPRT affects dendrite number or branching, abnormal dendrite number or branching may underlie the neurological symptoms of LNS and other related disorders. Although purine metabolic defects have not been well characterized in these patients, agents that increase dendrite number and/or branching may act to help these patients with memory. As a result, there is an immediate need for a sensitive assay for early diagnosis of cognitive disorders such as Alzheimer's disease, autism, Rett syndrome, Parkinson's disease, fetal alcohol syndrome, etc, as well as assays for identification of compounds to treat these and other cognitive disorders.
USPTO Backgrounds
USPTO Backgrounds