Brain-derived neurotrophic factor (BDNF) is one of neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. Although the expression of BDNF and its receptor TrkB still occurs in the adult stage, their physiological role in the mature CNS is not fully understood. In the present study we examined in detail the possibility that BDNF modulates synaptic neurotransmissions by using patch-clamp technique in rat hippocampal CA1 region. BDNF (20 -100 ng/ml) did not show any appreciable effect on evoked EPSCs, but it markedly reduced both evoked and spontaneous IPSCs within 5 min, and the reduction persisted while BDNF was present. BDNF also attenuated GABA A receptor-mediated response to applied GABA. However, BDNF failed to attenuate IPSCs when the postsynaptic pyramidal neuron was loaded intracellularly with 200 nM K252a, an alkaloid that inhibits the kinase activity of Trk receptor family, through the patch pipette. Intracellular application of 200 nM K252b, a weaker inhibitor of Trk-type kinase, did not affect the inhibition. The attenuating effect also was prevented by postsynaptic injection of U73122 (5 M), a broad-spectrum PLC inhibitor, and by strong chelation of intracellular Ca 2ϩ with 10 mM BAPTA. These data suggest that BDNF modulates GABA A synaptic responses by postsynaptic activation of Trk-type receptor and subsequent Ca 2ϩ mobilization in the CNS.Key words: BDNF; GABA A receptor; disinhibition; plasticity; LTP; hippocampus Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. During brain development neurotrophins and their receptors display distinct stage-and tissue-specific patterns of expression (Ernfors et al., 1990a;Phillips et al., 1990;Merlio et al., 1992). BDNF mRNA is observed in the embryonic stage and is still present in the postnatal and adult stages (Ernfors et al., 1990b;Maisonpierre et al., 1990; Freidman et al., 1991). In the adult stage its expression level is modulated dramatically by neuronal activity (Falkenberg et al., 1992;Patterson et al., 1992;Rocamora et al., 1992;Bengzon et al., 1993;Kokaia et al., 1993). Moreover, expression of TrkB, a functional BDNF receptor, not only increases during embryonic development but also continues to increase until several weeks after birth in the hippocampus (Masana et al., 1993;Ringstedt et al., 1993). These observations suggest that in the adult CNS dynamic change in BDNF level still can trigger neuronal plasticity via activation of TrkB. Indeed, neurotrophins are secreted by neurons in both a constitutive and an activity-dependent manner Thoenen, 1995, 1996;Griesbeck et al., 1995;Thoenen, 1995;Goodmann et al., 1996). Additionally, BDNF induces long-lasting enhancement of synaptic transmission (Kang and Schuman, 1995) and facilitates the induction of long-term potentiation (LTP) in the hippocampus (Figurov et al., 1996); however, the site and mechanism of action of BDNF remain unclear, becau...

Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integrity of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is overexpressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss of p53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification.

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The pX sequcncc of human T cell Icukcmia virus type I (HTLV-I) has been thought to bc cxprcsscd as a doubly spliced mRNA thal codes for p40lax. p27rcx and p21X. However. WC identified a novel allcrnativcly spliced mRNA in the HTLV-I infccvd cells by using rcvcrsc transcription rollowed by the polymcrasc chain rcaction. This mRNA conlains only the firs1 and third cxons of the doubly spliced mRNA and encodes only p2lX. Our data thaw this mRNA is rcsponsiblc for expressing p2lX exists in most or HTLV-I infcclcd cells strongly suggcs~s that p2lX may play a crucial role for HTLV .I rcplicalion.

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