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. 2015 Apr 29;35(17):6893-902.
doi: 10.1523/JNEUROSCI.4002-14.2015.

Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice

Shreaya Chakroborty  1 , Joyce Kim  2 , Corinne Schneider  3 , Anthony R West  1 , Grace E Stutzmann  4
Affiliations

Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice

Shreaya Chakroborty et al. J Neurosci. .

Abstract

Synaptic plasticity deficits are increasingly recognized as causing the memory impairments which define Alzheimer's disease (AD). In AD mouse models, evidence of abnormal synaptic function is present before the onset of cognitive deficits, and presents as increased synaptic depression revealed only when synaptic homeostasis is challenged, such as with suppression of ryanodine receptor (RyR)-evoked calcium signaling. Otherwise, at early disease stages, the synaptic physiology phenotype appears normal. This suggests compensatory mechanisms are recruited to maintain a functionally normal net output of the hippocampal circuit. A candidate calcium-regulated synaptic modulator is nitric oxide (NO), which acts presynaptically to boost vesicle release and glutamatergic transmission. Here we tested whether there is a feedforward cycle between the increased RyR calcium release seen in presymptomatic AD mice and aberrant NO signaling which augments synaptic plasticity. Using a combination of electrophysiological approaches, two-photon calcium imaging, and protein biochemistry in hippocampal tissue from presymptomatic 3xTg-AD and NonTg mice, we show that blocking NO synthesis results in markedly augmented synaptic depression mediated through presynaptic mechanisms in 3xTg-AD mice. Additionally, blocking NO reduces the augmented synaptically evoked dendritic calcium release mediated by enhanced RyR calcium release. This is accompanied by increased nNOS levels in the AD mice and is reversed upon normalization of RyR-evoked calcium release with chronic dantrolene treatment. Thus, recruitment of NO is serving a compensatory role to boost synaptic transmission and plasticity during early AD stages. However, NO's dual role in neuroprotection and neurodegeneration may convert to maladaptive functions as the disease progresses.

Keywords: calcium; homeostasis; nitric oxide; ryanodine receptor; synaptic depression; synaptic plasticity.

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Figures

Figure 1.
Figure 1.
NO maintains long term potentiation in young 3xTg-AD mice. A, B, Graph shows averaged time course of LTP from NonTg and 3xTg-AD mice in aCSF (A) and l-NAME (B). Insets, Baseline traces before (1) and after (2) HFS from NonTg (black) and 3xTg-AD (gray) mice. C, Bar graph shows percentage change in post-HFS response relative to baseline 0–2 min after HFS (PTP), 15–20 min after HFS (E-LTP), and 50–60 min after HFS (L-LTP). The arrow denotes the time at which the HFS (2 × 100 Hz, 10 s apart) was administered; *p < 0.05 indicates significantly different from NonTg; **p < 0.05 indicates significantly different from control aCSF-treated slices.
Figure 2.
Figure 2.
NO maintains long term depression in young 3xTg-AD mice. A–C, Graph shows averaged time course of LTD from NonTg and 3xTg-AD mice in aCSF (A), l-NAME (B), and SNAP (C). Insets, Representative baseline traces before (1) and after (2) LFS from NonTg (black) and 3xTg-AD (gray) mice. D, Bar graph shows percentage change in post-LFS responses relative to baseline 0–2 min after LFS (STD), 15–20 min after LFS (E-LTD), and 50–60 min after LFS (L-LTD). The arrow denotes the time at which the LFS (900 pulses at 1 Hz) was administered; *p < 0.05 indicates significantly different from NonTg; **p < 0.05 indicates significantly different from control aCSF-treated slices.
Figure 3.
Figure 3.
NOS inhibition normalizes neurotransmitter release in 3xTg-AD neurons. A–C, Representative traces of postsynaptic spontaneous potentials recorded from NonTg (black) and 3xTg-AD (gray) CA1 neurons in aCSF (A), l-NAME (B), and SNAP (C). D, E, Bar graphs show averaged frequency (D) and amplitude (E) of spontaneous events from NonTg and 3xTg-AD neurons in aCSF, l-NAME and SNAP before (baseline) and 20 min after LFS (E-LTD); *p < 0.05 indicates significantly different from NonTg; **p < 0.05 indicates significantly different from control aCSF-treated neurons.
Figure 4.
Figure 4.
NO increases probability of neurotransmitter release. A, Representative PPF traces at 50 ms interpulse interval from NonTg (black) and 3xTg-AD (gray) neurons. B, PPF measured at indicated interstimulus intervals. Bar graph shows paired-pulse ratio for NonTg and 3xTg-AD neurons in aCSF, l-NAME and SNAP before (baseline) and 20 min after LFS (E-LTD); *p < 0.05 indicates significantly different from NonTg; **p < 0.05 indicates significantly different from control aCSF-treated neurons; ***p < 0.05 indicates significantly different from baseline.
Figure 5.
Figure 5.
NOS inhibition decreases synaptically evoked calcium responses in 3xTg-AD CA1 neurons. A, Pseudocolored images of dendritic calcium response from a NonTg neuron in aCSF to 30 Hz stimulus before LFS (baseline), 1 min after LFS (STD), and 20 min after LFS (E-LTD). B–D, Same as in A, but from l-NAME-treated NonTg neuron (B), a 3xTg-AD neuron in aCSF (C), and 3xTg-AD neuron treated with l-NAME (D). E, Bar graphs comparing averaged maximal calcium changes between NonTg and 3xTg-AD neurons with and without l-NAME or SNAP after 30 Hz stimulus at baseline, STD and E-LTD time-points. Inset, Calcium traces from NonTg/aCSF (black), NonTg/l-NAME (gray), NonTg/SNAP (light gray), 3xTg-AD/aCSF (red), 3xTg-AD/l-NAME (orange), and 3xTg-AD/SNAP (yellow) neurons; *p < 0.05 indicates significantly different from NonTg neurons; **p < 0.05 indicates significantly different from control aCSF-treated neurons.
Figure 6.
Figure 6.
Increased nNOS protein expression in 3xTg-AD mice. A, Western blot showing hippocampal nNOS protein levels in saline- or dantrolene-treated NonTg and 3xTg-AD mice. B, Bar graph shows nNOS protein levels relative to β-actin controls; *p < 0.05 indicates significantly different from NonTg; **p < 0.05 indicates significantly different from dantrolene-treated mice.
Figure 7.
Figure 7.
Proposed role of NO signaling in early synaptic homeostasis and later neurodegeneration at the CA3–CA1 synapse in AD. Normal: NO generated by nNOS in the postsynaptic CA1 terminal diffuses to the presynaptic CA3 terminal and modulates neurotransmitter release. Early AD: increased RyR expression significantly increases CICR (calcium-induced calcium release). At the presynaptic terminal, RyR-evoked CICR can facilitate spontaneous neurotransmitter release. Increased RyR-evoked calcium also drives increased nNOS production, which in turn, generates increased levels of NO that, diffuses to the presynaptic terminal. Increased CICR and NO signaling mediate increased release of neurotransmitter vesicles to maintain normal levels of plasticity. Late AD: sustained increases in RyR-evoked calcium signaling and NO signaling can deplete vesicles from the readily releasable pool, as well as the reserve pool and cause metabolic, oxidative and nitrosative stress, mitochondrial and ER dysfunction, and ultimately loss of synapses and neuronal death. Further, NO can aberrantly S-nitrosylate several proteins that eventually also contribute to neurodegeneration.
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