Elsevier

Ageing Research Reviews

Volume 3, Issue 4, November 2004, Pages 407-430
Ageing Research Reviews

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

https://doi.org/10.1016/j.arr.2004.07.002Get rights and content

Abstract

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. We describe experiments that reveal the critical role of cAMP/protein kinase A and MAP kinase pathways, and the downstream transcription factor CREB. Because transcription-dependent long-term changes are input specific, we also discuss the role of “local protein synthesis” and “synaptic tagging” mechanisms that may confer synapse specificity. We then focus on brain-derived neurotrophic factor (BDNF) and tissue plasmigonen activator (tPA), two secreted proteins that have been repeatedly implicated in L-LTP. Biochemical and molecular biology experiments indicate that the expression and secretion of both factors are enhanced by strong tetanic stimulation that induces L-LTP as well as by training in hippocampal-dependent memory tasks. Inhibition of either tPA or BDNF by gene knockout and specific inhibitors results in a significant impairments in L-LTP and long-term memory. Further work will be required to address the relationship between BDNF and tPA in various forms of synaptic plasticity, and the mechanisms by which BDNF/tPA achieves synapse-specific modulation. Finally, we discuss how the aging process affects L-LTP and long-term memory.

Introduction

A remarkable feature of the brain is to store and recall a seemingly endless series of events and experiences in life. This capacity, known as memory, is critically dependent on the hippocampus and related limbic structures (Milner et al., 1998, Eichenbaum, 2000). Hippocampal-dependent memory can be divided into two temporally and mechanistically distinct forms: a short-term form lasting seconds to tens of minutes, and a long-term form that persists for hours, days and even weeks. A key feature that sets apart long-term from short-term memory is its dependence on new protein synthesis (Squire and Barondes, 1973). Combined cellular and behavioral studies suggest that learning and memory can be modeled by long-term potentiation (LTP), an electrophysiological measure of sustained increase in synaptic efficacy at hippocampal synapses. The memory-related changes in synaptic strength can also be divided into two temporally and mechanistically distinct phases. A single train of high frequency stimulation (tetanus, 100 Hz, 1 s), which mimics the physiological bursts of neuronal activity in mammalian hippocampus, induces an increase in synaptic efficacy that lasts for 1–2 h. This form of plasticity, called early phase LTP (E-LTP), involves modifications of pre-existing synapses as a result of rapid Ca2+ influx through NMDA type glutamate receptor and subsequent protein phosphorylation events (Bliss and Collingridge, 1993, Malenka and Nicoll, 1999). In contrast, repeated high-frequency stimulation at certain intervals (e.g., four trains of tetanus at every 10 min) results in long-lasting, late-phase LTP (L-LTP) that lasts as long as the recordings can be maintained (6–8 h) (Frey et al., 1988). This longer lasting form of synaptic plasticity requires activation of cAMP-dependent protein kinase (PKA) and the transcription factor CREB (Kandel, 2001). Moreover, L-LTP is dependent on new protein synthesis, similar to long-term memory. Pharmacological inhibition of protein synthesis completely blocks L-LTP (Stanton and Sarvey, 1984, Frey et al., 1988). While the expression of a number of proteins is enhanced in response to L-LTP inducing tetanic stimulation (Qian et al., 1993, Matsuo et al., 2000, Ingi et al., 2001), the specific protein synthesis product(s) responsible for the induction and maintenance of L-LTP remain to be identified.

One of the tetanus-induced proteins that has received a great deal of attention in recent years is brain-derived neurotrophic factor (BDNF), a member in the neurotrophin family of secretory proteins. While initially identified as a survival factor for peripheral neurons, BDNF has emerged as a critical secretory protein that regulates synaptic development and plasticity in the CNS (Poo, 2001, Lu, 2003). In cultured hippocampal neurons, acute application of BDNF elicits rapid changes in synaptic transmission at both excitatory and inhibitory synapses (Lessmann et al., 1994, Levine et al., 1995, Brunig et al., 2001, Baldelli et al., 2002), and these effects are mediated by either pre- or post-synaptic mechanisms (Lessmann and Heumann, 1998, Levine et al., 1998, Li et al., 1998). Gene knockout studies demonstrated that BDNF is required for hippocampal E-LTP (Korte et al., 1995, Patterson et al., 1996). It has been shown that BDNF facilitates hippocampal E-LTP by potentiating synaptic response to LTP-inducing tetanus and an enhancement of synaptic vesicle docking, possibly through changes in the levels and/or phosphorylation of synaptic proteins (Figurov et al., 1996, Gottschalk et al., 1998, Pozzo-Miller et al., 1999, Jovanovic et al., 2000). In addition to its acute effects on synaptic transmission and plasticity, BDNF also exhibits a long-term regulatory role in synapse structure and function. Long-term application of BDNF exerts complex modulation of dendritic and axonal growth in neurons of the CNS (Cohen-Cory and Fraser, 1995, McAllister et al., 1995). BDNF is involved in activity-dependent synaptic competition and formation of ocular dominance columns in the visual cortex (Cabelli et al., 1995, Cabelli et al., 1997). Long-term regulation of synaptic transmission by BDNF has also been observed in glutamatergic and GABAergic synapses in the CNS (Rutherford et al., 1998, Vicario-Abejon et al., 1998, Huang et al., 1999, Sherwood and Lo, 1999). Taken together, the capacity of BDNF to regulate the structure and function of hippocampal synapses makes BDNF an attractive candidate protein mediating L-LTP.

Another tetanus-induced protein known to be involved in L-LTP is the extracellular serine protease tissue-plasminogen activator (tPA). tPA is an extracellular serine protease, which is widely expressed in the CNS including hippocampus (Qian et al., 1993, Salles and Strickland, 2002). Induction of L-LTP enhances the transcription of tPA in the hippocampus (Qian et al., 1993). tPA can be secreted from neuronal growth cone and axonal terminals (Krystosek and Seeds, 1981), and neuronal membrane depolarization also induces secretion of tPA into the extracellular space in the hippocampus in a Ca2+-dependent manner (Gualandris et al., 1996). Activation of cAMP/PKA pathway also induces the secretion of tPA (Baranes et al., 1998). In hippocampal cultures, tPA acts extracellularly to stimulate the elongation of the axons of granule neurons, and induces the formation of functionally competent glutamatergic synapses consisting of an active, pre-synaptic secretory component and a post-synaptic recognition component enriched with glutamate receptors (Baranes et al., 1998). The main enzymatic actions of tPA are to convert inactive precursor plasminogen to the active protease plasmin (Plow et al., 1995); and to degrade certain components in extracellular matrix (Chen and Strickland, 1997, Wu et al., 2000). More recently, tPA has been demonstrated to be involved in activity-related formation of perforated synapses in the hippocampus (Neuhoff et al., 1999). Thus, tPA could also serve as a potential mediator of L-LTP.

In this review, we will discuss the cellular and molecular mechanisms underlying L-LTP in the context of long-term memory. We will also describe how aging process affects L-LTP and long-term memory. In particular, we will focus on two secreted proteins BDNF and tPA, and discuss in detail the genetic, biochemical and physiological evidence supporting their role in L-LTP, and the possible underlying mechanisms.

Section snippets

Molecular mechanisms of L-LTP and long-term memory

LTP has been adopted as a cellular model for the study of learning and memory since its discovery in the early 1970s. After three decades of intensive research, we have come much closer in understanding the cellular and molecular mechanisms underlying LTP. In particular, we have known a great deal about the mechanisms for the induction of E-LTP (Bliss and Collingridge, 1993, Malenka and Nicoll, 1999). In brief, the induction process involves the activation of NMDA receptors, a subclass of

Regulation of L-LTP and long-term memory by BDNF

As discussed above, genes induced by L-LTP stimuli are considered as candidates that mediate the long-term synaptic plasticity. Thus, the first clue that BDNF may be involved in long-term synaptic plasticity came from the demonstration that the expression of BDNF mRNA is enhanced by the LTP-inducing tetanic stimulation in CA1 (Patterson et al., 1992) and dentate gyrus (Castren et al., 1993, Dragunow et al., 1993) (see Lu, 2003, for review). The fact that the activity-dependent BDNF

Regulation of L-LTP and memory by tPA

Is tPA one of the target genes responsible for L-LTP expression and long-term memory? An important criterion is whether tPA is expressed and/or secreted in an activity-dependent manner. Qian et al. have provided the first direct evidence for the enhancement of tPA mRNA expression by neuronal activity in hippocampus (Qian et al., 1993). With three different stimulation paradigms which independently evoke seizure, kindling or L-LTP, they found that the level of tPA mRNA is increased rapidly and

L-LTP and long-term memory in aging

Aging is tightly associated with memory impairments (for review see Rosenzweig and Barnes, 2003). Disruption of any one of the stages in the memory mechanism – acquisition, consolidation or retention – could lead to memory dysfunction. While deterioration in brain anatomy, physiology, plasticity and network dynamics could contribute to age-related memory deficits, the most reliable cellular system to address the effects of aging on long-term memory experimentally is hippocampal L-LTP. In fact,

Perspectives

Compared with E-LTP, much less is known about the cellular and molecular mechanisms underlying L-LTP. PKA and MAPK are widely accepted as the two key signaling pathways for L-LTP, but exactly how they translate the brief, high frequency stimulation into sustained structural and functional changes at the hippocampal synapses requires further investigation. Although substantial experimental data support the notion that protein synthesis and the transcription factor CREB are important for L-LTP,

Acknowledgements

We thank Dr. Newton Woo for critical reading of the manuscript. The work from authors’ laboratory is supported by NICHD intramural program.

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