conditioning. However, neither spatial learning in mice, nor short-term memory (learning) in Drosophila seems to be affected by the absence of tau. In addition, tau knockout mice have abnormal sleep-wake cycle, with increased wakefulness periods and decreased non-rapid eye movements (NREM) sleep time. Other functions Other typical functions of tau include cellular signalling, neuronal development, neuroprotection and apoptosis. Atypical, non-standard roles of tau are also under current investigation, such as its involvement in chromosome stability, its interaction with the cellular transcriptome, its interaction with other cytoskeletal or synaptic proteins, its involvement in myelination or in brain insulin signaling, its role in the exposure to chronic stress and in depression, etc. Genetics In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively spliced, which leads to the formation of six tau isoforms. In the human brain, tau proteins constitute a family of six isoforms with a range of 352–441 amino acids. Tau isoforms are different in having either zero, one, or two inserts of 29 amino acids at the N-terminal part (exons 2 and 3) and three or four repeat-regions at the C-terminal part (exon 10). Thus, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total). The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copies of the gene, resulting in congenital defects. Structure Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with