Glucocorticoids are often prescribed following brain injury

Glucocorticoids are often prescribed following brain injury. prototypical member of a family of structurally related proteins including brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5. Neurotrophins have been identified in many vertebrate lineages, including reptiles, amphibians, fish, birds, and mammals [1]. Not all neurotrophins have been found in all species; NT-4/5 has not been found in chicken and NT-6 and -7 are found only in fish. More distantly related genes have been found in theAgnathaspecies lamprey and hagfish. Phylogenetic analysis indicates that NGF and NT-3 form a subfamily as TCS ERK 11e (VX-11e) do BDNF and NT-4/5. The neurotrophins bind two classes of receptor, the common p75NTR, which is a member of the tumor necrosis factor receptor family [2,3], and the tropomyosin-related kinase (Trk) receptors, members of the large tyrosine kinase receptor family [4]. Three Trk receptors have been identified in vertebrates, and more distantly related receptors have been found in lamprey and amphioxus. TrkA and TrkC form a distinct phylogenetic subfamily [1]. All neurotrophins bind p75NTR with comparable affinity (Kd~10-9M), but binding to the Trk receptors is usually more selective. NGF binds the TrkA receptor, BDNF and NT-4/5 bind the TrkB receptor, and NT-3 primarily binds the TrkC receptor [5]. These binding specificities are consistent with the phylogenetic separation into distinct subfamilies. NT-6 and -7 are more closely related to NGF than the other neurotrophins and bind TrkA [1]. The common p75NTR also enhances binding of NGF to TrkA receptors to create high affinity binding sites (Kd~10-11M), possibly by binding to different surfaces around the NGF dimer [6]. p75NTR can also bind precursor forms of the neurotrophins. For example, pro-NGF does not bind TrkA, but causes cell death by binding to p75NTR [7,8]. These neurotrophins function to support the growth and survival of many neuronal populations [5,9-11]. NGF-deficient mice die shortly after birth and show a decrease in sensory and sympathetic neurons, but basal forebrain cholinergic neurons develop relatively normally. However, this perinatal lethality can be rescued by transgenic expression of NGF under the K14 keratin TCS ERK 11e (VX-11e) promoter, which restores the sensory and sympathetic neuronal populations [12]. These rescued mice exhibit reduced cholinergic innervation in the cortex and hippocampus, but this can be restored by intracerebroventricular delivery of NGF [13]. Disruption of a single NGF allele causes deficits in memory acquisition and hippocampal cholinergic innervation, suggesting that NGF is required for the formation and maintenance of correct innervations [14]. BDNF-deficient mice also die shortly after birth due to defects in brain and sensory, but not motor, neuron development [15]. Long-term potentiation and TCS ERK 11e (VX-11e) mechanosensation are impaired in heterozygous BDNF knockout animals [16,17]. NT-3 deficient mice show severe movement defects and die shortly after birth with complete absence of spinal proprioceptive afferents [18]. The number of muscle spindles was reduced in heterozygous NT-3 knockout mice. NT-3 deficiency also causes a decrease in the number of sympathetic cervical ganglion neurons, lingual innervations, and sensory neuron precursor cells [19,20]. The three Trk receptors show distinct patterns of expression throughout the mammlian brain and peripheral nervous system [4,21-24]. TrkA is usually expressed exclusively by cholinergic neurons in the basal TCS ERK 11e (VX-11e) forebrain. TrkB and TrkC are highly expressed in the hippocampus. In the peripheral nervous system, these receptors are expressed on overlapping sets of sensory and motor neurons. None of the Trk receptors are essential for embryonic development and knockout mice are given birth to in the expected ratios. However, the mice fail to thrive and die shortly after birth. TrkA-deficient mice show a marked Rabbit Polyclonal to RPL26L loss of cholinergic neurons in the forebrain and sensory and sympathetic neurons in the trigeminal, superior cervical, and dorsal root ganglia [25-28]. Mice lacking TrkB show decreased synaptogenesis and mossy fiber maturation in the hippocampus, as well as severe sensory deficits in the vestibular and cochlear ganglia [29-31]. TrkC-deficient mice also show decreased hippocampal synaptogenesis and display abnormal movements due to loss of proprioception and muscle afferents [30-32]. Heterozygosity for atrkallele permits survival, but structural alterations are apparent in aged mice [14,33,34]. TrkC is also expressed on non-neuronal cells and supports glial development [35]..