Extracellular and intracellular cleavages of proBDNF required at two distinct stages of late-phase LTP.

Although late-phase long-term potentiation (L-LTP) is implicated in long-term memory, its molecular mechanisms are largely unknown. Here we provide evidence that L-LTP can be divided into two stages: an induction stage (I) and a maintenance stage (II). Both stages require mature brain-derived neurotrophic factor (mBDNF), but involve distinct underlying mechanisms.

Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis.

Alemtuzumab, a monoclonal antibody directed against human CD52, is used in the treatment of MS. To characterize the impact of anti-CD52 administration, a monoclonal antibody to mouse CD52 (anti-muCD52) was generated and evaluated in EAE mouse models of MS. A single course of anti-muCD52 provided a therapeutic benefit accompanied by a reduction in the frequency of autoreactive T lymphocytes and production of pro-inflammatory cytokines.

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes.

Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory.

While deregulation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neurodegenerative diseases, its precise role in synaptic plasticity and memory remains elusive. Proteolytic cleavage of p35, a regulatory subunit of Cdk5, by calpain results in the generation of the truncated p25 protein, which causes hyperactivation of Cdk5. Using region-specific and inducible transgenic mice, we show that transiently increased p25 expression in the hippocampus enhanced long-term potentiation (LTP) and facilitated hippocampus-dependent memory.

The yin and yang of neurotrophin action.

Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75NTR).

Activation of p75NTR by proBDNF facilitates hippocampal long-term depression.

Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75(NTR)) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75(NTR), facilitates hippocampal long-term depression (LTD).

Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons.

Synaptic actions of brain-derived neurotrophic factor (BDNF) are 'gated' by cyclic AMP (cAMP), but the underlying molecular mechanisms remain unclear. Here we report that cAMP regulates BDNF function in mature hippocampal neurons by modulating the signaling and trafficking of its receptor TrkB. cAMP gated the TrkB tyrosine kinase with three characteristic features: BDNF-induced TrkB phosphorylation was attenuated by inhibitors of cAMP signaling, it was potentiated by cAMP analogs, and activation of the cAMP pathway alone had no effect.

Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF.

Long-lasting forms of memory are generally believed to be mediated by protein synthesis-dependent, late-phase long-term potentiation (L-LTP). L-LTP exhibits at least two distinctive characteristics compared with early phase LTP (E-LTP): synaptic growth and requirement of gene transcription and new protein synthesis. In this review, we discuss the cellular and molecular mechanisms underlying the structural and functional changes of hippocampal synapses during L-LTP, in the context of long-term memory.

Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity.

Long-term memory is thought to be mediated by protein synthesis-dependent, late-phase long-term potentiation (L-LTP). Two secretory proteins, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), have been implicated in this process, but their relationship is unclear. Here we report that tPA, by activating the extracellular protease plasmin, converts the precursor proBDNF to the mature BDNF (mBDNF), and that such conversion is critical for L-LTP expression in mouse hippocampus.