Mol Psychiatry︱ Gao Tianming's research group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory

Author ︱ Gao Tianming, edited by Liu Jihong ︱ Wang Sizhen Long-term potentiation (LTP) in the hippocampus is the most studied type of synaptic plasticity, and it is also considered to be a cellular mechanism of learning and memory [1]
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LTP can be divided into early LTP (E-LTP) and late LTP (L-LTP) according to the length of its maintenance time.
E-LTP is induced by a single high-frequency stimulation (HFS) and the maintenance time is about 1 hour [2], L-LTP is induced by multiple high-frequency stimulations and lasts for more than 1 hour [3]
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Although in the past 20 years, researchers have done a lot of research on the molecular mechanism of LTP, but its cellular mechanism is still unclear
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The expression of synaptic plasticity requires the integration of calcium signals induced by presynaptic afferents at postsynaptic
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The calcium signal of neurons is usually maintained within a few milliseconds, while the calcium signal in astrocytes can be maintained for several seconds to several minutes.
This feature can connect neuronal information from different time and space to achieve a higher level Information integration
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And do these two cell types also play different roles in synaptic plasticity and learning and memory? This issue is currently unclear
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 On October 12, 2021, Tianming Gao’s research group of Southern Medical University published a research paper entitled "Distinct roles of astroglia and neurons in synaptic plasticity and memory" in Molecular Psychiatry, and proposed a star The different roles of glial cells and neurons in LTP and memory
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Liu Jihong, Zhang Meng and Wang Qian are the co-first authors of the paper, and Professor Tianming Gao is the corresponding author of the paper
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In this study, the authors found that by integrating presynaptic afferents, the calcium signal of astrocytes is essential for L-LTP, a process of brain-derived neurotrophic factor released by astrocytes (Brain-derived neurotrophic factor, BDNF) mediated
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The neuron-derived BDNF is important for both E-LTP and L-LTP
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Further mechanism studies have shown that the difference in the kinetics of BDNF released by the two types of cells may be the cause of different forms of LTP
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Moreover, BDNF from different cell sources also plays different roles in memory
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This article enriches our understanding of synaptic plasticity and memory at the cellular level, and reveals the different roles of astrocytes and neurons in integrating synaptic information
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(Extended reading: The latest research by Gao Tianming's group, see "Logic Neuroscience" report for details: JCI︱ Gao Tianming's group reveals that the prefrontal cortex has an opposite role in regulating anxiety and fear.
) Many previous studies have shown that stars The calcium signal of glial cells is essential for regulating synaptic plasticity [5-8]
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The inositol triphosphate type 2 receptor (IP3R2) on the endoplasmic reticulum is an important source of calcium signal in astrocytes
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However, studies have reported that knocking out this receptor does not affect E-LTP [9], and further question whether the calcium signal of astrocytes is involved in regulating synaptic plasticity
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Here, the author first used IP3R2 whole body knockout mice (IP3R2-KO) and recorded LTP in the CA1 area of ​​adult hippocampal slices, and found that the induction of E-LTP was not affected, while L-LTP was significantly inhibited (Figure 1)
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This suggests that the calcium signal mediated by IP3R2 in astrocytes is involved in the regulation of L-LTP
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To further prove this hypothesis, the author used Cre-loxp technology to conditionally knock out IP3R2 (IP3R2-cKO) on astrocytes and record LTP.
It was also found that L-LTP was damaged but E-LTP was not affected.
Impact (Figure 1)
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The above evidence indicates that the calcium signal mediated by astrocyte IP3R2 is very important for L-LTP
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Figure 1 Calcium signal mediated by astrocyte IP3R2 is very important for L-LTP (picture quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) Then whether the above phenomenon is induced by astrocytes to L-LTP -Is it mediated by the integration of calcium signals generated by multiple series of high-frequency stimulations of LTP? With this question in mind, the author combined two-photon and electrophysiological techniques to record L-LTP while observing the changes in the calcium signal of astrocytes in the CA1 region of the hippocampus
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The authors found that in the process of inducing L-LTP in wild-type mice, astrocytes have the effect of integrating calcium signals, while the integration effect disappeared in IP3R2-KO and IP3R2-cKO mice (Figure 2 ), indicating that the integration of calcium signal in astrocytes under high-frequency stimulation is involved in regulating the induction of L-LTP
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Figure 2 The integration of astrocytes on the calcium signal generated by multiple series of high-frequency stimuli that induce L-LTP (picture quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) Figure 3 Astrocytes The source of BDNF is necessary for L-LTP (picture quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) Astrocytes participate in the regulation of nerves by releasing active molecules such as glutamate, D-serine and ATP Physiological functions of meta-and synapses [10]
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And BDNF can be synthesized and released in astrocytes, and plays an important role in L-LTP [11]
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In order to verify whether BDNF is involved in the regulation of L-LTP by astrocytes, the author further knocked out BDNF on astrocytes (aBDNF-cKO)
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Like the IP3R2 knockout mice mentioned above, the induction of L-LTP is impaired after knocking out BDNF on astrocytes, and after BDNF is overexpressed on the astrocytes of this mouse, its L-LTP LTP returned to normal levels (Figure 3), indicating that BDNF derived from astrocytes is necessary for L-LTP
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So what function does neuron-derived BDNF play? The author then specifically knocked out the BDNF (nBDNF-cKO) on the neuron and found that both E-LTP and L-LTP were damaged.
After BDNF was overexpressed in the mouse neuron, the E-LTP and L -LTP is normal (Figure 4), indicating that BDNF derived from neurons is important for both E-LTP and L-LTP
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When the ELISA technology was used to observe the release of BDNF at different time points during the L-LTP induction process of the above-mentioned transgenic mice, the authors found that the duration of BDNF release on the brain slices of IP3R2-cKO and aBDNF-cKO mice was significantly shorter, while nBDNF -cKO mice reduced the amplitude and duration of BDNF release.
Exogenous administration of BDNF to interfere with these changes can reverse the damage of LTP (Figure 5), indicating that the release kinetics of BDNF participates in the regulation of different forms of LTP
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Figure 4 Neuron-derived BDNF is important for both E-LTP and L-LTP (picture quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) Figure 5 BDNF release kinetics is involved in the regulation of different forms of LTP (figure Quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) LTP in the hippocampus is very critical for the formation of memory
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The author next used the conditioned fear memory model and found that after knocking out IP3R2 or BDNF on astrocytes, the long-term memory of the mice was impaired, and after knocking out the BDNF on the neurons, the mice could not be in the training phase.
Effective learning, while short-term memory and long-term memory are also hindered, and after BDNF is overexpressed in the corresponding cells, the learning and memory will return to normal levels (Figure 6)
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These evidences indicate that BDNF from different cell sources regulates different forms of memory
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Figure 6 BDNF from different cell sources regulates different forms of memory (picture quoted from: Liu, JH.
et al.
, Mol Psychiatry, 2021) Conclusion and discussion, inspiration and outlook Photonic and genetic manipulation techniques have found that the calcium signal mediated by IP3R2 on astrocytes regulates L-LTP by integrating multiple series of HFS-induced calcium signals, and this process is mediated by the release of BDNF from astrocytes
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This result supports the long-term role of astrocytes in integrating information and discovers a new function of astrocytes in synaptic plasticity
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At the same time, we also saw that the author divided L-LTP into two parts: L-LTP1 (2 hours after induction) and L-LTP2 (3 hours after induction), and further analyzed the L-LTP of IP3R2-cKO and aBDNF-cKO mice.
LTP found that both L-LTP1 and L-LTP2 of IP3R2-cKO mice were damaged, while only L-LTP2 of aBDNF-cKO mice was damaged
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The author speculates that BDNF produced by astrocytes mainly regulates L-LTP2, and L-LTP1 may be mediated by astrocytes recovering the precursor BDNF (pro-BDNF) produced by neurons and processing and releasing [12] This speculation needs further experimental proof
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 The neuron-derived BDNF is important for both E-LTP and L-LTP.
Among them, L-LTP may also be the precursor BDNF (pro-BDNF) released by neurons, which is mediated by the processing and release of BDNF on astrocytes [ 12]
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In other words, it is very likely that BDNF released by neurons is mainly involved in E-LTP, while L-LTP is mainly regulated by astrocytes, and the relevant evidence needs further study
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In short, this study found for the first time that different cells have different roles in regulating synaptic plasticity and memory, and it also suggests that astrocytes and neurons play different roles in information integration
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