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Long-Term Potentiation at CA3-CA1 Hippocampal Synapses with Special Emphasis on Aging, Disease, and Stress.

Kumar A - Front Aging Neurosci (2011)

Bottom Line: Synaptic plasticity in the mammalian central nervous system has been the subject of intense investigation for the past four decades.LTP is regarded as a principal candidate for the cellular mechanisms involved in learning and offers an attractive hypothesis of how memories are constructed.There are a number of exceptional full-length reviews published on LTP; the current review intends to present an overview of the research findings regarding hippocampal LTP with special emphasis on aging, diseases, and psychological insults.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida Gainesville, FL, USA.

ABSTRACT
Synaptic plasticity in the mammalian central nervous system has been the subject of intense investigation for the past four decades. Long-term potentiation (LTP), a major reflection of synaptic plasticity, is an activity-driven long-lasting increase in the efficacy of excitatory synaptic transmission following the delivery of a brief, high-frequency train of electrical stimulation. LTP is regarded as a principal candidate for the cellular mechanisms involved in learning and offers an attractive hypothesis of how memories are constructed. There are a number of exceptional full-length reviews published on LTP; the current review intends to present an overview of the research findings regarding hippocampal LTP with special emphasis on aging, diseases, and psychological insults.

No MeSH data available.


Related in: MedlinePlus

Enhance AHP amplitude during aging contributes to impaired LTP induction. (A) Representative intracellular current clamp recordings from a CA1 hippocampal pyramidal neuron in aged rat are shown after a train of five action potentials elicited by a 100-ms pulse of depolarizing current under conditions of CPA (3 μM) and following bath application of Bay K8644 (1 μM) in the presence of CPA. Note that under conditions of blockade of Ca2+ release from intracellular calcium stores by CPA, the L-channel agonist, Bay K8644 increased the AHP amplitude. (B) Time course of the synaptic responses following 5 Hz pattern stimulation in presence of Bay K8644 + CPA. LTP induced by 5 Hz stimulation was blocked under conditions of Bay K8644 + CPA in which AHP amplitude was increased (adapted from Kumar and Foster, 2004).
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Figure 4: Enhance AHP amplitude during aging contributes to impaired LTP induction. (A) Representative intracellular current clamp recordings from a CA1 hippocampal pyramidal neuron in aged rat are shown after a train of five action potentials elicited by a 100-ms pulse of depolarizing current under conditions of CPA (3 μM) and following bath application of Bay K8644 (1 μM) in the presence of CPA. Note that under conditions of blockade of Ca2+ release from intracellular calcium stores by CPA, the L-channel agonist, Bay K8644 increased the AHP amplitude. (B) Time course of the synaptic responses following 5 Hz pattern stimulation in presence of Bay K8644 + CPA. LTP induced by 5 Hz stimulation was blocked under conditions of Bay K8644 + CPA in which AHP amplitude was increased (adapted from Kumar and Foster, 2004).

Mentions: The idea that induction of LTP is subdued as a result of a reduction in NMDA receptor activation during aging is supported by research showing that induction deficits can be overcome by strong postsynaptic depolarization (Barnes et al., 1996). Indeed, there are several reasons to believe that an inability to achieve sufficient postsynaptic depolarization, a prerequisite for NMDA receptor activation, may be more problematic for LTP induction during senescence. First, the reduced synaptic strength of aged animals may result in a reduced afferent cooperativity in depolarizing the postsynaptic neuron and an inability to reach the level of depolarization needed for NMDA receptor activation. Moreover, it has been proposed that the inability to depolarize the cell is compounded during patterned stimulation, due to the larger after hyperpolarization (AHP). In fact, results suggest that it is the relatively large AHP which underlies much of the LTP impairment found in these animals (Foster and Norris, 1997; Foster, 1999). Our work demonstrates that large AHP amplitude may mask the propensity of enhanced LTP induction during senescence (Kumar and Foster, 2004). Normally, there is a relationship between the frequency of afferent stimulation required for LTP induction and the level of resulting depolarization (Froemke et al., 2005), but during aging this is obscured by an increase in the Ca2+-dependent, K+-mediated AHP (Landfield and Pitler, 1984; Pitler and Landfield, 1990; Moyer et al., 1992; Disterhoft et al., 1996; Kumar and Foster, 2002; Tombaugh et al., 2005; Bodhinathan et al., 2010a). During aging, the large AHP may disrupt the integration of depolarizing postsynaptic potentials and the duration of this disruption has been proposed to be a function of the extent and duration of the AHP (Foster and Norris, 1997; Foster, 1999; Foster and Kumar, 2002). Hypothetically, the disruption would increase the level of stimulation needed for LTP, resulting in a plateau in the frequency-response function. In fact, our studies along with others, have demonstrated that the AHP amplitude is intimately involved in regulating the threshold for induction of LTP (Sah and Bekkers, 1996; Norris et al., 1998; Cohen et al., 1999; Sourdet et al., 2003; Kramar et al., 2004; Kumar and Foster, 2004; Le Ray et al., 2004; Murphy et al., 2004; Xu and Kang, 2005; Fuenzalida et al., 2007). Further, other evidence shows that pharmacological manipulations that reduce the AHP amplitude also shift the frequency-response functions, such that LTP can be observed following stimulation frequencies that would normally not elicit LTP. For example, pharmacological blockade of L-type Ca2+ channels, inhibition of Ca2+ release from ICS, or attenuation of K+ channels enables the induction of LTP following a modest stimulation in aged animals (Figure 3; Norris et al., 1998; Kumar and Foster, 2004). Similarly, our work also demonstrates that LTP can be inhibited by enhancement in the amplitude of the AHP following treatment with the L-channel agonist, Bay K8644 (Figure 4; Kumar and Foster, 2004). Although L-channel activity should provide more Ca2+, the induction of LTP is impaired due to L-channel-induced enhancement in the AHP amplitude. Thus, it is interesting to note that, while induction of LTP depends on a large rise in intracellular Ca2+, LTP induction is facilitated by blocking several Ca2+ sources that contribute to the AHP during senescence.


Long-Term Potentiation at CA3-CA1 Hippocampal Synapses with Special Emphasis on Aging, Disease, and Stress.

Kumar A - Front Aging Neurosci (2011)

Enhance AHP amplitude during aging contributes to impaired LTP induction. (A) Representative intracellular current clamp recordings from a CA1 hippocampal pyramidal neuron in aged rat are shown after a train of five action potentials elicited by a 100-ms pulse of depolarizing current under conditions of CPA (3 μM) and following bath application of Bay K8644 (1 μM) in the presence of CPA. Note that under conditions of blockade of Ca2+ release from intracellular calcium stores by CPA, the L-channel agonist, Bay K8644 increased the AHP amplitude. (B) Time course of the synaptic responses following 5 Hz pattern stimulation in presence of Bay K8644 + CPA. LTP induced by 5 Hz stimulation was blocked under conditions of Bay K8644 + CPA in which AHP amplitude was increased (adapted from Kumar and Foster, 2004).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102214&req=5

Figure 4: Enhance AHP amplitude during aging contributes to impaired LTP induction. (A) Representative intracellular current clamp recordings from a CA1 hippocampal pyramidal neuron in aged rat are shown after a train of five action potentials elicited by a 100-ms pulse of depolarizing current under conditions of CPA (3 μM) and following bath application of Bay K8644 (1 μM) in the presence of CPA. Note that under conditions of blockade of Ca2+ release from intracellular calcium stores by CPA, the L-channel agonist, Bay K8644 increased the AHP amplitude. (B) Time course of the synaptic responses following 5 Hz pattern stimulation in presence of Bay K8644 + CPA. LTP induced by 5 Hz stimulation was blocked under conditions of Bay K8644 + CPA in which AHP amplitude was increased (adapted from Kumar and Foster, 2004).
Mentions: The idea that induction of LTP is subdued as a result of a reduction in NMDA receptor activation during aging is supported by research showing that induction deficits can be overcome by strong postsynaptic depolarization (Barnes et al., 1996). Indeed, there are several reasons to believe that an inability to achieve sufficient postsynaptic depolarization, a prerequisite for NMDA receptor activation, may be more problematic for LTP induction during senescence. First, the reduced synaptic strength of aged animals may result in a reduced afferent cooperativity in depolarizing the postsynaptic neuron and an inability to reach the level of depolarization needed for NMDA receptor activation. Moreover, it has been proposed that the inability to depolarize the cell is compounded during patterned stimulation, due to the larger after hyperpolarization (AHP). In fact, results suggest that it is the relatively large AHP which underlies much of the LTP impairment found in these animals (Foster and Norris, 1997; Foster, 1999). Our work demonstrates that large AHP amplitude may mask the propensity of enhanced LTP induction during senescence (Kumar and Foster, 2004). Normally, there is a relationship between the frequency of afferent stimulation required for LTP induction and the level of resulting depolarization (Froemke et al., 2005), but during aging this is obscured by an increase in the Ca2+-dependent, K+-mediated AHP (Landfield and Pitler, 1984; Pitler and Landfield, 1990; Moyer et al., 1992; Disterhoft et al., 1996; Kumar and Foster, 2002; Tombaugh et al., 2005; Bodhinathan et al., 2010a). During aging, the large AHP may disrupt the integration of depolarizing postsynaptic potentials and the duration of this disruption has been proposed to be a function of the extent and duration of the AHP (Foster and Norris, 1997; Foster, 1999; Foster and Kumar, 2002). Hypothetically, the disruption would increase the level of stimulation needed for LTP, resulting in a plateau in the frequency-response function. In fact, our studies along with others, have demonstrated that the AHP amplitude is intimately involved in regulating the threshold for induction of LTP (Sah and Bekkers, 1996; Norris et al., 1998; Cohen et al., 1999; Sourdet et al., 2003; Kramar et al., 2004; Kumar and Foster, 2004; Le Ray et al., 2004; Murphy et al., 2004; Xu and Kang, 2005; Fuenzalida et al., 2007). Further, other evidence shows that pharmacological manipulations that reduce the AHP amplitude also shift the frequency-response functions, such that LTP can be observed following stimulation frequencies that would normally not elicit LTP. For example, pharmacological blockade of L-type Ca2+ channels, inhibition of Ca2+ release from ICS, or attenuation of K+ channels enables the induction of LTP following a modest stimulation in aged animals (Figure 3; Norris et al., 1998; Kumar and Foster, 2004). Similarly, our work also demonstrates that LTP can be inhibited by enhancement in the amplitude of the AHP following treatment with the L-channel agonist, Bay K8644 (Figure 4; Kumar and Foster, 2004). Although L-channel activity should provide more Ca2+, the induction of LTP is impaired due to L-channel-induced enhancement in the AHP amplitude. Thus, it is interesting to note that, while induction of LTP depends on a large rise in intracellular Ca2+, LTP induction is facilitated by blocking several Ca2+ sources that contribute to the AHP during senescence.

Bottom Line: Synaptic plasticity in the mammalian central nervous system has been the subject of intense investigation for the past four decades.LTP is regarded as a principal candidate for the cellular mechanisms involved in learning and offers an attractive hypothesis of how memories are constructed.There are a number of exceptional full-length reviews published on LTP; the current review intends to present an overview of the research findings regarding hippocampal LTP with special emphasis on aging, diseases, and psychological insults.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida Gainesville, FL, USA.

ABSTRACT
Synaptic plasticity in the mammalian central nervous system has been the subject of intense investigation for the past four decades. Long-term potentiation (LTP), a major reflection of synaptic plasticity, is an activity-driven long-lasting increase in the efficacy of excitatory synaptic transmission following the delivery of a brief, high-frequency train of electrical stimulation. LTP is regarded as a principal candidate for the cellular mechanisms involved in learning and offers an attractive hypothesis of how memories are constructed. There are a number of exceptional full-length reviews published on LTP; the current review intends to present an overview of the research findings regarding hippocampal LTP with special emphasis on aging, diseases, and psychological insults.

No MeSH data available.


Related in: MedlinePlus