Potential Adaptive Function for Altered Long-Term Potentiation Mechanisms in Aging Hippocampus

Abstract

Age-dependent alterations in the induction of long-term potentiation (LTP) are well documented, providing a likely neural basis for memory decline associated with aging. Studies of neural plasticity are also important to understand the neural basis of individual differences in aging, ranging from significant cognitive impairment to preservation of function on a par with younger adults. To examine the cellular mechanisms that distinguish such outcomes, we studied the induction of LTP in male outbred young and aged rats behaviorally characterized in hippocampal-dependent spatial learning. We evaluated, in vitro, the magnitude of NMDA receptor (NMDAR)-dependent and -independent forms of LTP induced in the Schaffer collateral to CA1 synapses. We found that age substantially reduces NMDAR-dependent LTP across the spectrum of cognitive outcomes, whereas increased NMDAR-independent LTP occurs distinctively in high-performing aged rats. Moreover, in young rats, behavioral performance correlates strongly with the magnitude of NMDAR-LTP, whereas NMDAR-independent LTP correlates with behavioral performance only in aged rats. Together with similar previous findings on the mechanisms for LTD in this model, these results support the notion that a shift from NMDAR-dependent to NMDAR-independent mechanisms for neural plasticity during aging is associated with better cognitive outcomes.

Reversal of aging‐associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function

“…It is well documented that NMDAR activation plays an essential role in the induction of LTP, and NMDAR hypofunction is observed in aged animals or patients with age-related neurodegenerative diseases (Barnes et al, 1997;Shankar et al, 1998;Clayton et al, 2002;Mothet et al, 2006;Battaglia et al, 2007;Turpin et al, 2009). More evidence indicates that the alterations in NMDAR functional properties are primarily responsible for aging-associated deficits of synaptic plasticity (Potier et al, 2000;Clayton et al, 2002;Boric et al, 2008;Turpin et al, 2009). Interestingly, this impaired NMDAR-dependent synaptic plasticity in aged animals was reversed by upregulation of NMDAR activity using pharmacological approach (Mothet et al, 2006).…”

“…In fact, VDCCs are assumed to be activated by higher-stimulation frequencies than those activating NMDARs (Morgan & Teyler, 1999). Thus, to induce the NMDAR-dependent LTP, theta-burst stimulation (TBS, containing two trains of five pulses at 100 Hz separated by 200 ms), a type of more physiological relevant stimulus, is introduced (Raymond, 2007;Boric et al, 2008). The LTP of neurotransmission was measured by the changes in field excitatory postsynaptic potentials (fEPSPs) before and after TBS in the CA1 area of the hippocampus.…”

“…Synaptic plasticity, especially the long-term potentiation (LTP) in hippocampus, is widely considered as a key cellular mechanism underlying learning and memory. Generally, many studies have revealed that an impairment of hippocampal LTP usually occurs in aged animals, and this kind of impairment is thought to be the basis of AAMI (Watson et al, 2002;Mothet et al, 2006;Boric et al, 2008).…”

“…The hypofunction of NMDAR is primarily responsible for deficits in synaptic plasticity in aged animals or patients with age-related neurodegenerative diseases (Barnes et al, 1997;Shankar et al, 1998;Potier et al, 2000;Clayton et al, 2002;Mothet et al, 2006;Battaglia et al, 2007). Moreover, recent studies demonstrate that the alteration in NMDAR functional properties, rather than in their expression or density, is the mechanism of age-related deficits in NMDAR (Potier et al, 2000;Clayton et al, 2002;Boric et al, 2008;Turpin et al, 2009). Interestingly, D-serine, an amino acid that serves as an endogenous ligand for the strychnine-insensitive glycine-binding site of NMDAR, rescues the impaired NMDARdependent synaptic plasticity in aged animals (Mothet et al, 2006), suggesting that the upregulation of NMDAR activity by pharmacological approach can reverse age-associated impairment of synaptic function.…”

Neurobiological Bases of Learning and Their Role for the Paradigm Shift in Education

“…Since the studies of facial migration, long term potentiation and depression, and the demonstration of neurogenic niches (Altman, 1969), the paradigm of learning and neuronal remodeling has changed (Bliss, Collingridge, & Morris, 2014;Neves, Cooke, & Bliss, 2008). Within Kirkwood's work we can see the importance of a cellular and molecular base for the concept of andragogy, which redefines the way we learn (Boric, Munoz, Gallagher, & Kirkwood, 2008;Yang et al, 2013). Cellular studies have clearly shown that stimuli that generate changes in conduct are reinforced or replicated in fear or aggression systems, as well as pleasure systems.…”