Aluminum-Induced Electrophysiological Variation, Synaptic Plasticity Impairment,
9.2 Al-Induced Electrophysiological Variation
9.2.4 The Cell Signal Pathways and Aluminum Effect on Synaptic Plasticity
Neurobiological basis of LTP in the hippocampus is the changes in neurons that is synaptic plasticity, the material basis related to the changes of protein and gene in neurons and synapses [34]. It is well known that the formation of long-term memory
requires new gene transcription and subsequent new protein synthesis in the CNS, similar to the maintenance of LTP [35, 36]. The events of LTP, as known for NMDA receptor-dependent LTP, include series processes but not limited to postsynaptic NMDA receptor activation, postsynaptic calcium influx increase, and activation of several protein kinases, such as CaMKII, PKC PKA, and ERK [37]. The AMPAR is essential for brain function and plays an important role in changes in synaptic strength and connectivity [38]. During synaptic plasticity, changes in the content of AMPAR have been well demonstrated [43–45]. Recent studies have also shown that the activation of some signaling pathway in the hippocampus of rats plays a key role in long-term memory. It is reasonable to consider that the following signaling path- ways may also be important in the mechanism underlying Al-induced long-term memory impairment.
9.2.4.1 Glutamate-NO-cGMP and Aluminum Effect on Synaptic Plasticity
The neurotransmitter glutamate activates NMDA receptor and then postsynaptic calcium influx increase through coupling calcium channels. The calcium ion acti- vates nitric oxide synthase and catalyzes the synthesis of NO (nitric oxide), then NO activates guanylate cyclase to produce cGMP (cyclic guanosine monophosphate)
Table 9.1 Induction of NMDAR-dependent synaptic plasticity Model Basal transmission
Stimulation parameters
Change of transmission after the stimulus
LTP Low intracellular Ca2+
level (around 0.1 uM)
High-frequency stimulation (100–200 Hz)
High intracellular Ca2+ elevation (more than 10 uM)
Basal phosphorylation of S845 of AMPARs
Enhanced phosphorylation of S845 and exocytosis of AMPAR Very low phosphorylation
of S831 of AMPARs
Enhanced phosphorylation of S831 and unitary AMPAR channel conductance
Increased number of AMPAR in PSD;
Increased AMPAR peak current and synaptic strength
LTD Low intracellular Ca2+
level (around 0.1 uM)
Low-frequency stimulation (1 Hz)
Moderate intracellular Ca2+ elevation Basal phosphorylation of
S845 of AMPARs
Enhanced dephosphorylation of S845 and endocytosis of AMPAR
Very low phosphorylation of S831 of AMPARs
No significant change in
phosphorylation of S831 of AMPARs Decreased number of AMPAR in PSD
Decreased AMPAR peak current and synaptic strength
which finally plays a biological effect [39]. Canales [40] cultured neuron cells of 8–13 days by culture medium containing 50 umol/L aluminum chloride and found that contents of cGMP activated by glutamate decreased by 77%, and NO-cGMP glutamate signal transduction was severely damaged. In addition, aluminum also blocks this signal transduction by interference expression of NMDA receptor [41]
and Ca2+ [42], then the normal function of nerve cells was affected, and the motion performance and spatial memory’s function of mice were damaged.
9.2.4.2 PLC Signaling Pathway and Aluminum Effect on Synaptic Plasticity
The muscarinic receptors which are abundant in the hippocampus activate phospho- lipase systems (including PLAl, PLA2, PLC, PLD) and catalyze the formation of PIP2 through coupling the G protein. PIP2 is cleaved to form 1,4,5- IP3 and DAG. Water-soluble IP3 is released into the cytoplasm; then Ca2+ is released from the calcium pool to regulate calcium- and calmodulin-dependent enzymes and other
Table 9.2 Aluminum effect on synaptic plasticity
Experiment model Effect References
Wistar rat 7–8 weeks old (hippocampal slices)
0.68 μg/ml Al attenuated TEA LTP, while a complete block of long-lasting potentiation was obtained for 2.7 μg/ml Al
[29]
Wistar rat (80–100 days old) Al reduced the amplitudes of both EPSP LTP (control, 132 ± 7%, n = 7; Al-exposed, 115 ± 10%, n = 8, P < 0.05) and PS LTP (control, 242 ± 18%, n = 7; Al-exposed, 136 ± 7%, n = 8, P < 0.01) significantly
[30]
Wistar rat (80–100 days old) Aluminum exposure from parturition throughout life caused the greatest impairment of the range of synaptic plasticity
[31]
Great pond snail (right parietal dorsal 1 neuron)
Extracellular application of Al (100 μM) led to membrane depolarization, bursts of action potentials, and action potential broadening
[20]
Wistar rat (120–150 g) granule cell layer of dentate gyrus (freely moving animal with implanted electrodes); hippocampal (CA1) slices (transverse; 450 um)
Acute Al infusion at 0.68 and especially 2.7 μg/ml Al leads to a reduction in LTP, and the potentiation declined to baseline within 2 h. In chronic animals their neuronal responsiveness was reduced, and in 30% of the rats, the PS was completely lost.
High-frequency tetanization failed to induce LTP
[21]
SD rats (intraperitoneal injection for 8 weeks)
Al suppressed in vivo LTP and damaged spatial learning and memory capacities
[32]
SD rats (intraperitoneal injection for 8 weeks; via intracerebroventricular injection for 5 min)
Acute Al treatment produced dose- dependent suppression of LTP in the rat hippocampus
[33]
channels. DAG activates the membrane PKC. M1 receptor and the activity of GTP were significantly inhibited in hippocampus and cerebral cortex [50, 51]. Another research reported that the phosphorylation of phosphatidylinositol was inhibited when the rats experienced long-term exposure of drinking aluminum salt. Aluminum can decrease the content of PIP2, and IP3 in brain tissue also affects the expression and activity of PKC [43]. The signal molecules in PLC signaling pathway are not normally expressed or activated by aluminum, leading to the disorder of PLC sig- naling pathway, which makes damage of LTP.
9.2.4.3 Ca2+-CaM-CaMKII Signaling Pathway and Aluminum Effect on Synaptic Plasticity
Ca2+-CaM-CaMKII signaling pathway in the hippocampus of rats plays a key role in long-term memory. Aluminum is an antagonist of enzymes containing calcium and magnesium which can be replaced by aluminum. The activity of ATP enzymes such as calcium-dependent protein kinase was eventually inhibited [44]. Morae’s study found that aluminum competitively combined with calcium channel in the period of rapid flow of calcium ions in the competition, to prevent the influx of cal- cium ions [45]. Wang [42] found that aluminum inhibits the expression of CaMKII in the mouse brain and Ca2+-CaM-CaMKII signal transduction. At the same time, calcium is a second messenger and participates in the regulation of cellular process.
Once the cells are exposed to aluminum, cytoplasmic calcium homeostasis will be disturbed, the normal conduction pathway will be affected, and thus learning and memory will be impaired.
9.2.4.4 The MAPK Pathway and Aluminum Effect on Synaptic Plasticity There are four subtypes of MAPK, namely, extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK, also known as stress-activated MAPK), and ERK5. After the phos- phorylation of MAPK, MAPK can enter the nucleus and phosphorylate nuclear transcription factors, leading to the expression of downstream target genes and the synthesis of new proteins [46].
In recent years, many scholars have shown that the small GTPase RAS signaling pathway plays important roles in LTP and in formation and the consolidation of memories in the brain [47]. Appropriate activation of the Ras/extracellular signal- regulated kinase (ERK) protein signaling cascade within the brain is crucial for optimal learning and memory. The Ras GTPase-activating protein (RasGAP), which attenuates Ras/ERK signaling by converting active Ras, is bound to guanosine tri- phosphate, activating Ras into inactive Ras, and is bound to guanosine diphosphate, inactivating Ras. Then ERK is transferred to the nucleus to phosphorylate transcription factor, such as CREB which plays a biological effect in LTP [48]. A study [49] which is carried out by long-term consumption of aluminum-containing
food to mice found that protein and mRNA levels of Ras in neurons were increased;
at the same time, the protein and mRNA levels of rafl, ERK2, and CREB were hin- dered by aluminum. Aluminum affects the brain information storage and memory via Ras/ERK signal transduction [50]. Our previous study [51] found that with the increasing aluminum dosage, a gradually decreasing RAS activity of the rat hippo- campus was produced after gradually suppressing on LTP; the RAS→PI3K/
PKB→GluR1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats.
9.2.4.5 Wnt Pathway and Aluminum Effect on Synaptic Plasticity
As we know now, Wnt1, Wnt3a, Wnt7a, and Wnt8 bind the receptor Frizzled and the LRP5/6 co-receptors, activating the Wnt/ß-catenin [52]. Both Fz and LRP5/6 recruit the protein disheveled (Dvl) usually by phosphorylation, which oligomerizes in the plasma membrane forming a platform for the allocation of the scaffold pro- tein Axin and the glycogen synthase kinase-3ß (GSK-3ß) [53, 54]. The phosphory- lation of LRP5/6 causes the inhibition of GSK-3ß and adenomatous polyposis coli (APC). The consequence of this inhibition is the cytoplasmic stabilization of ß-catenin which enters the nucleus and regulates the transcription of Wnt target genes [55]. The activation of Wnt signaling increases synaptic transmission and facilitates LTP in hippocampal brain slices and in cultured neurons, suggesting a key role for Wnt signaling in the regulation of synaptic plasticity [56, 57]. Studies have shown that long-term exposure to aluminum environment could increase the activity of GSK-3ß and then inhibit the signal transduction [58]. Our previous study found that Al-induced LTP impairment might be related to the activation of GSK-3ß [59]. Researchers found that in PC 12 cells treated with aluminum maltolate,contents of Wnt3, DVL, and ß-catenin were decreased and finally Wnt/ß-catenin pathway was weakened [60].