SUMMARY The brain produces two brain-derived neurotrophic factor (BDNF) transcripts, with either short or long 3′ untranslated regions (3′UTR). The physiological significance of the two forms of mRNAs encoding the same protein is unknown. Here we show that the short and long 3′UTR BDNF mRNAs are involved in different cellular functions. The short 3′UTR mRNAs are restricted to somata whereas the long 3′UTR mRNAs are also localized in dendrites. In a mouse mutant where the long 3′UTR is truncated, dendritic targeting of BDNF mRNAs is impaired. There is little BDNF in hippocampal dendrites despite normal levels of total BDNF protein. This mutant exhibits deficits in pruning and enlargement of dendritic spines, as well as selective impairment in long-term potentiation in dendrites, but not somata, of hippocampal neurons. These results provide insights into local and dendritic actions of BDNF and reveal a mechanism for differential regulation of subcellular functions of proteins.

Mutations in the Bdnf gene, which produces transcripts with either short or long 3′ untranslated regions (3′UTRs), cause human obesity; however, the precise role of BDNF in the regulation of energy balance remains unknown. Here we show the relationship between long 3′UTR Bdnf mRNA, leptin, neuronal activation and body weight. We found that long 3′UTR Bdnf mRNA was enriched in dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3′UTR developed severe hyperphagic obesity, which was completely rescued by viral expression of long 3′UTR Bdnf mRNA in the hypothalamus. In these animals the ability of leptin to activate hypothalamic neurons and to inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.

Huntington’s disease (HD), a dominantly inherited neurodegenerative disorder characterized by relatively selective degeneration of striatal neurons, is caused by an expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels of brain‐derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF gene expression and anterograde transport of BDNF from cortex to striatum. However, roles of the BDNF reduction in HD pathogenesis have not been established conclusively. We reasoned that increasing striatal BDNF through over‐expression would slow progression of the disease if BDNF reduction plays a pivotal role in HD pathogenesis. We employed a Bdnf transgene driven by the promoter for the alpha subunit of Ca2+/calmodulin‐dependent kinase II to over‐express BDNF in the forebrain of R6/1 mice which express a fragment of mutant htt with a 116‐glutamine tract. The Bdnf transgene increased BDNF levels and TrkB signaling activity in the striatum, ameliorated motor dysfunction, and reversed brain weight loss in R6/1 mice. Furthermore, it normalized DARPP‐32 expression of the 32 kDa dopamine and cAMP‐regulated phosphoprotein, increased the number of enkephalin‐containing boutons, and reduced formation of neuronal intranuclear inclusions in the striatum of R6/1 mice. These results demonstrate crucial roles of reduced striatal BDNF in HD pathogenesis and suggest potential therapeutic values of BDNF to HD.

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Astroglial b-adrenergic receptors (b-ARs) are functionally linked to regulate cellular morphology. In primary cultures, the b-AR agonist isoproterenol (ISP) can transform flat polygonal astrocytes into process-bearing, mature stellate cells by 48 h, an effect that can be blocked by the b-AR antagonist, propranolol. ISP induced immediate activation of protein kinase A (PKA) which persisted up to 2 h, with no visible change in cell morphology. However, activation of PKA was sufficient to drive the process of transformation to completion, suggesting the involvement of downstream regulators of PKA. In addition to PKA inhibitors, the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 also blocked ISP-induced morphological transformation. ISP treatment resulted in a biphasic response of cellular phosphorylated MAPK (phosphorylated extracellular signal-regulated kinase; p-ERK) level: an initial decline in p-ERK level followed by a sustained induction at 12-24 h, both of which were blocked by PKA inhibitor. The induction in pERK level coincided with initiation of morphological differentiation of the astrocytes and nuclear translocation of p-ERK. A long-lasting activation of p-ERK activity by ISP, at a later stage, appears to be critical for the transformation of astrocytes. Keywords: astrocyte, b-adrenergic receptors, mitogen-activated protein kinase, morphology, protein kinase A, protein kinase C.