Enhancement of LTP in Aged Rats is Dependent on Endogenous BDNF

Abstract

Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A(2A) receptors (A(2A)R), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A(2A)R antagonist, SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.

Neuromuscular transmission modulation by adenosine upon aging

“…In the central nervous system, the neuromodulatory action of adenosine and the expression of its membrane receptors change with age (see Diógenes et al, 2011;Sebastião and Ribeiro, 2009). So, it was considered of interest to investigate the role of adenosine at the neuromuscular junction, as a function of age, looking at the relative importance of adenosine A 1 receptors vis-a-vis adenosine A 2A receptors.…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…These results suggest that activating the cholinergic system in aged animals may enhance cognitive function and physical activity. Ageing leads to decreased release of growth and neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF; Diogenes et al, 2011;Niewiadomska et al, 2011). These alterations during ageing inhibit neurogenesis and thereby accelerate shrinkage of the hippocampus (Karege et al, 2002), which is associated with behavioral and functional deficits in hippocampus-dependent learning and memory tasks (Rosenzweig and Barnes, 2003).…”

“…In contrast, BDNF and NGF promote survival of developing cholinergic forebrain neurons and attenuate the loss of neurons following excitotoxic insults (Burke et al, 1994;Sofroniew et al, 2001). In addition, NGF upregulates several cholinergic markers (Pongrac and Rylett, 1998;Oosawa et al, 1999;Auld et al, 2001), and BDNF is required for maturation of cholinergic nerves and plays a critical role in longterm potentiation required for memory consolidation (Ward and Hagg, 2000;Diogenes et al, 2011).…”

Adenosine A2A receptor activation is determinant for BDNF actions upon GABA and glutamate release from rat hippocampal synaptosomes

“…The different actions of A 2A Rs in different synapses and their ability to affect different actions of BDNF at specific sites of the tripartite synapse may allow to finely shape excitatory and inhibitory signals, thus to fine tune neuronal function. This probably has a greater impact upon synaptic plasticity rather than upon neuroprotection since BDNF actions on plasticity are known to be controlled by A 2A R [7,13,14], whereas neuroprotective actions of BDNF may not be affected by A 2A Rs [26].…”

“…Accordingly, there is evidence that activation of A 2A R induces the transactivation of TrkB-FL receptors [5,6], TrkB-FL translocation to lipid rafts [7], and regulates BDNF [8] and TrkB-FL levels [9]. Regarding functional evidence, it is clear that the facilitatory actions of BDNF upon CA1 hippocampal synaptic transmission [8,[10][11][12] and synaptic plasticity, both long-term potentiation [9,13,14] and long-term depression [15], are dependent on A 2A R activation. CA1 hippocampal synaptic activity relies, in part, on the dynamics of the most relevant neurotransmitters in this brain region, glutamate and GABA.…”