Introduction
Post-stroke depression (PSD), a common neuropsychological disorder with
a prevalence of up to one-third of post-stroke complications, has a
serious negative impact on the life, psychology, and recovery of
patients with stroke (Villa et al. 2018). As its prevalence has
increased, numerous clinical trials have identified risk factors for
PSD, including age, gender, history of depression, stroke severity, and
lesion site (Cheng et al. 2018). However, its pathogenesis and available
pharmacological treatments remain unclear. Therefore, the exploration of
the pathological mechanisms underlying PSD and the search for effective
treatments are of great significance.
Although a large number of mechanisms have been proposed to explain the
occurrence of PSD, including abnormalities in the
hypothalamus-pituitary-adrenal axis (Farrell et al. 2018), inflammatory
response (Ferrucci and Fabbri 2018), monoaminergic hypothesis (van Praag
et al. 1973), neurotrophic hypothesis, and altered neuroplasticity
(Castren and Monteggia 2021), the specific biological mechanisms remain
unclear. Neuroplasticity has received increasing attention in the study
of affective disorders-like symptoms. Studies have shown that neuronal
apoptosis and synaptic dysfunction in cortical limbic brain regions can
induce depression (Chia et al. 2020). The hippocampus, an important
cortical limbic brain region for neurogenesis, is the most common brain
region used in depression research. Numerous studies have found that the
development of depressive disorders is associated with hippocampal
neuroplasticity, including changes in the hippocampal structure,
neuronal apoptosis, and reduced neurogenesis (Ishikawa et al. 2019).
Hippocampal synaptic alterations underlie altered neuronal plasticity.
In the central nervous system, synaptic alterations occur because of
changes in synaptic morphology and function due to synaptic plasticity,
mainly long-term synaptic plasticity, including long-term potentiation
(LTP) and long-term depression (LTD) (Kasai et al. 2017). In
stress-induced depression-like rats, hippocampal LTP is impaired whereas
LTD is facilitated, and this process can be reversed by antidepressant
drugs (Liu et al. 2017). In addition, hippocampal volume decreases in
mice after stroke, and neurons undergo apoptosis (Amtul et al. 2014; Li
et al. 2021). This suggests that hippocampal neuroplasticity plays a key
role in post-stroke depressive disorder (Figure 1).
Recent studies have found that brain-derived neurotrophic factor (BDNF)
participates in synaptogenesis by modulating different postsynaptic
receptors and activating downstream signaling (Missale et al. 1998).
Moreover, this modulation has a bidirectional effect on PSD (Wang et al.
2021; Yang et al. 2021). The autophosphorylating
Ca2+/calmodulin-dependent protein kinase II (CaMKII),
an enzyme associated with hippocampal synaptic plasticity, is involved
in LTP and LTD processes (Yasuda et al. 2022). In hippocampal
astrocytes, the gap-junction protein connexin 43 (Cx43) and its linker
protein regulate synaptic activity (Murphy-Royal et al. 2020). In
addition, neurotransmitters and their receptors associated with synaptic
activity also play a key role in hippocampal processes involved in PSD
(Ji et al. 2014). In this article, we discuss the role of these factors
in modulating hippocampal synaptic plasticity during PSD. This enables
us to better understand the specific molecular mechanisms of altered
hippocampal synaptic plasticity in
PSD.
Neurotrophic factors regulate synaptic plasticity
BDNF is a neurotrophic cytokine that plays an important role in the
central nervous system. It not only regulates synaptic plasticity and
neuronal development but is also an important factor in the regulation
of mood disorders (Wang et al. 2022).
Berton et al. found in various
animal models of depression that BDNF levels in the nucleus accumbens of
depression model rats remained unchanged or even increased (Berton et
al. 2006; Dandekar et al. 2019), whereas BDNF levels in the hippocampus
decreased (Rahmani et al. 2020; Wang et al. 2023). Pro-BDNF is a BDNF
precursor that is cleaved into mature BDNF (Wang et al. 2021). Clinical
studies have found that serum levels of BDNF in patients with depression
were decreased, whereas pro-BDNF levels were increased (Gelle et al.
2020). Furthermore, in post-stroke patients, BDNF levels were lower in
the serum than in patients without depression, and depressive symptoms
were alleviated by antidepressant drugs or exogenous BDNF (Zhang and
Liao 2020). The mechanism related to mood regulation by BDNF in the
hippocampus is mainly accomplished by acting on different receptors to
regulate hippocampal synaptic plasticity (Kowianski et al. 2018; Micheli
et al. 2018a; Nutt 2008). BDNF can promote LTP induction in the
hippocampus in conjunction with the tropomyosin receptor kinase B (TrkB)
(Nibuya et al. 1995), and conversely pro-BDNF can promote apoptosis of
neuronal cells and inhibit LTP occurrence in conjunction with the p75
neurotrophin receptor (p75NTR) (Luo et al. 2019) (Figure 2). This
strongly suggests that BDNF in the hippocampus is involved in the onset
of depression after stroke by regulating synaptic plasticity.
BDNF–TrkB promotes LTP
BDNF in the hippocampus is involved in the physiological and
pathological processes of depression by targeting TrkB receptors to
regulate LTP (Kozisek et al. 2008; Zhang et al. 2016). A study found
lower protein and mRNA levels of BDNF and TrkB in the hippocampus by
comparing the brains of people who had died by suicide due to depression
with those of people who had died in traffic accidents (Chhibber et al.
2017a; Erbay et al. 2021). Decreased BDNF and TrkB expression in the
hippocampus was also found in a mouse model of corticosterone-induced
depression, and antidepressant treatment ameliorated this pathological
change (Erbay et al. 2021). The treatment of PSD mice with the TrkB
antagonist ANA-12 reduced the benefits of antidepressant drugs (Ren et
al. 2021). Related studies have reported that both BDNF–TrkB signaling
and the corresponding expression levels were attenuated in the
hippocampus in a rat model of PSD, and antidepressant drug treatment or
other physical treatments stimulated this signaling pathway (Jiang et
al. 2021a; Kang et al. 2021). Similarly, in depression induced by
hemorrhagic stroke, the BDNF–TrkB pathway plays a key role (Infantino
et al. 2022). A recent clinical investigation in China showed that TrkB
gene polymorphisms were significantly associated with PSD (Liang et al.
2018; Zhou et al. 2015).
Both BDNF and TrkB are involved in depression by inhibiting LTP in the
hippocampus (Graciano et al. 2014). In the synapse, BDNF acts on pre-
and postsynaptic TrkB receptors, and the postsynaptic effect is
responsible for the strong induction of LTP by BDNF (Graciano et al.
2014). In the hippocampus, BDNF binds to postsynaptic TrkB receptors,
leading to TrkB autophosphorylation. This induces phosphorylation of
multiple receptors and increases synaptic transmission by activating
several intracellular signaling pathways, including Ras–MAPK,
PI3K–AKT, and PLC-γ–Ca2+ (Kowianski et al. 2018; Leal et al. 2017).
All these pathways can enhance dendritic growth and differentiation of
hippocampal neurons and induce neuronal signaling (Graciano et al. 2014;
Harward et al. 2016; Yang et al. 2021) (Figure 2). However, BDNF exerts
different effects upon TrkB activation. One study found that exogenous
BDNF delivery to cultured hippocampal neurons in both acute and gradual
modes induced transient and sustained activation of TrkB, respectively,
and the two different activation pathways had different effects, with
the former enhancing synaptic transmission and the latter promoting LTP
(Ji et al. 2010). Despite their different mechanisms of action, both
approaches can activate TrkB and are closely related to PSD.
High-frequency neuronal stimulation can increase sustained induction of
TrkB phosphorylation caused by external BDNF administration (Guo et al.
2018). Thus, increasing the sustained induction of TrkB phosphorylation
by BDNF can promote LTP in synaptic plasticity and is an important
mechanism involved in the treatment of depression after stroke.
Pro-BDNF–p75NTR induces LTD
Another BDNF-related receptor is p75NTR, which can bind BDNF to regulate
synaptic plasticity and induce LTD in hippocampal synapses. However,
recent studies have revealed that pro-BDNF, a precursor of BDNF,
exhibits a high affinity for p75NTR (Hashimoto 2016). In contrast to the
facilitatory effects TrkB has on neurons, p75NTR can bind pro-BDNF to
induce neuronal apoptosis (Teng et al. 2005). In a recent study, a PSD
model was established using oxygen and glucose deprivation and
corticosterone treatment (Yang et al. 2021). In this PSD model, the
number of apoptotic hippocampal neurons was significantly increased, and
these neurons had a significantly lower number of dendritic spines than
the control group (Yang et al. 2021). Moreover, both pro-BDNF and p75NTR
receptors were upregulated in the PSD model. These results demonstrate
that the binding of pro-BDNF to p75NTR promotes neuronal apoptosis and
thereby induces PSD. Another study found that antidepressants improved
depression-like behavior and decreased pro-BDNF and p75NTR expression in
the hippocampus of rats exposed to chronic unpredictable mild stress
(CUMS) (Yang et al. 2020; Yu et al. 2020). Aerobic exercise prevented
depression-like behavior in PSD rats while promoting BDNF mRNA
expression in the ischemic hippocampus and inhibiting pro-BDNF signaling
(Luo et al. 2019). Martinowich et al. found that acute stress had no
effect on LTD in hippocampal synaptic plasticity in p75NTR-deficient
mice, suggesting that p75NTR can influence emotion-related behaviors by
modulating hippocampal LTD (Martinowich et al. 2012). The administration
of antibodies directed against pro-BDNF in the hippocampus was found to
be effective in improving depression-like behavior in rats (Zhong et al.
2018). Interestingly, the mechanism of p75NTR action on hippocampal LTD
is different in the hippocampus of adult and juvenile rats (Martinowich
et al. 2012) as these effects are more pronounced in juvenile hippocampi
(Yang et al. 2009). This indicates that the mechanism of
pro-BDNF–p75NTR signaling in neuronal synapses in the hippocampus is
age-dependent. Many studies have demonstrated that pro-BDNF interacts
with p75NTR to induce neuronal apoptosis, leading to a reduction in the
number of neurons, which induces the onset of PSD (Koshimizu et al.
2009; Luo et al. 2019; Yang et al. 2014). Therefore, the imbalance
between BDNF–p75NTR and BDNF–TrkB signaling pathways causes apoptosis
of hippocampal neurons and affects synaptic regeneration, which may be
an important mechanism of PSD pathogenesis.
NMDA receptors regulate hippocampal synaptic plasticity
LTP and LTD are the main processes involved in hippocampal neuronal
synaptic plasticity. Both LTP and LTD cannot be activated without
N-methyl-D-aspartate (NMDA)-type receptor (NMDAR) channels (Hammond et
al. 1994). However, different subtypes of NMDARs may be involved in
different forms of hippocampal synaptic plasticity. Studies have shown
that pro-BDNF–p75NTR signaling enhances NMDAR-related subunit
NR2B-dependent LTD, as well as their mediated synaptic currents
(Bartlett et al. 2007; Woo et al. 2005). Another NMDAR subunit isoform,
NR2A, is not only involved in LTP development but also plays a role in
LTD induction (Abarzua et al. 2019; Philpot et al. 2007).
Pharmacological treatment was found to improve neurological deficits and
depressive symptoms by modulating NMDAR channels via BDNF–TrkB
signaling in a PSD rat model (Zhao et al. 2021). In a recent clinical
trial, serum positivity for NMDAR1-antibodies in patients with acute
ischemic stroke was associated with neuropsychiatric symptoms (Deutsch
et al. 2021). A related study found that NMDAR upregulation decreases
the levels of the synaptic structure-related marker PSD-95, as well as
other synaptic proteins associated with synaptic transmission (Wang et
al. 2022). These studies provide ample evidence of the regulatory role
of BDNF-related receptors in synaptic plasticity which play an important
role in the onset and development of PSD.
Participation of CREB in PSD
The cAMP response element-binding protein (CREB) is both a
BDNF-associated target and a transcription factor that regulates BDNF.
It plays a regulatory role in the development of PSD. CREB signaling was
diminished in the hippocampus of PSD rats, whereas the administration of
antidepressant drugs increased CREB signaling activity and improved
depression-like behavior in PSD rats (Jiang et al. 2021b). The
expression of molecules involved in the hippocampal neuroplasticity of
mice is upregulated shortly after treatment with antidepressants (Sun et
al. 2021). This occurs mainly through the activation of BDNF–TrkB
signaling to induce CREB phosphorylation (Odaira et al. 2019). This
suggests that CREB can act as a downstream target of BDNF–TrkB in the
development of PSD. Furthermore, CREB-mediated gene transcription is
also extensive. CREB regulates BDNF transcription in the hippocampus
through Ser133 phosphorylation thereby regulating its activity and
participation in LTP induction (Amidfar et al. 2020). In a study of mice
exposed to chronic unpredictable mild stress (CUMS), reduced hippocampal
CREB phosphorylation and BDNF protein expression and impaired CREB-BDNF
signaling were observed in these mice (Tan et al. 2022). Other studies
found that hippocampal CREB phosphorylation is inhibited under chronic
stress (Huang et al. 2019) and that with the inhibition of CREB
phosphorylation, extracellular signal-regulated kinase (ERK) activity is
also reduced (Qi et al. 2008; Wang et al. 2018). In mice treated with
antidepressants, ERK signaling increases the expression levels of BDNF
and phosphorylated CREB (Sun et al. 2021; Yao et al. 2022), suggesting a
regulatory role for CREB–BDNF in depression. In conclusion, the
occurrence of PSD is closely related to hippocampal BDNF and CREB
expression and is mainly achieved by regulating BDNF–CREB-related
signaling.
Based on the knowledge regarding the role of BDNF in the hippocampus and
its related targets in PSD, we can conclude that the occurrence and
development of PSD are closely related to altered hippocampal synaptic
plasticity induced by BDNF and its related signaling in the hippocampus.
CaMKII in the
hippocampus regulates PSD
CaMKII regulates synaptic plasticity
The group of CaMKs, kinases activated by Ca2+ and calmodulin (CaM),
mainly includes CaMKI, CaMKII, CaMKIII, and CaMKIV (Zhang et al. 2021).
Among them, CaMKII (mainly CaMKIIα
and CaMKIIβ) is expressed at the highest level in the brain, especially
in the hippocampus, and has been for many years a key area of research
on neuropsychiatric disorders (Shen et al. 2022). The role of CaMKII in
neuronal plasticity is structurally accomplished through the structural
domain of kinases containing phosphorylation sites and the central
structural domain (Robison 2014). At the synapse, including the pre- and
postsynaptic membranes, autophosphorylated CaMKII can regulate a variety
of protein activities, which further affect the regulation of synaptic
plasticity (Salaciak et al. 2021), including LTP and LTD.
CaMKII is involved in synaptic plasticity through its phosphorylation,
followed by its interaction with postsynaptic glutamate-related
receptors. First, in the excitatory synapses of hippocampal neurons,
glutamatergic LTP stimulation allows Ca2+ entry into neurons through
GluN2B-containing NMDARs to promote binding of Ca2+ with CaM which then
activates CaMKIIα (Lisman 2017) through phosphorylation of Thr286.
ISubsequently, CaMKIIα acts on NMDAR (mainly GluN2B)-associated protein
synthesis (Lisman et al. 2012; Shioda and Fukunaga 2017) and induces LTP
in excitatory synapses. Second, phosphorylated CaMKII is transferred to
the postsynaptic density and phosphorylates the AMPA receptor (AMPAR)
glutamate receptor 1 (GluA1) at Ser831 and increases its number, leading
to an increase in postsynaptic currents (Lisman et al. 2012). Both
pathways suggest that CaMKII Thr286 phosphorylation can maintain LTP by
acting on postsynaptic receptors and related proteins. Finally, CaMKII
was found to regulate synaptic plasticity through autophosphorylation
and Ca2+-dependent phosphorylation in addition to its involvement in the
release of neuropeptides and neuromodulators from dense core vesicles in
axons and dendrites (Moro et al. 2020). In addition to maintaining and
promoting LTP, CaMKII Thr286 phosphorylation can inhibit synaptogenesis
and participate in LTD, a process that cannot be separated from the
phosphorylation of Ser567, another locus of the glutamate receptor GluA1
(Coultrap et al. 2014).
CaMKII can engage LTP in postsynaptic hippocampal neurons following
excitatory stimulation due to Ca2+ influx, but the translocation of
phosphorylated CaMKII from the cytoplasm to postsynaptic densities
differs depending on the level of excitatory conditions (Tao-Cheng
2020). By modulating CaMKII autophosphorylation in the mouse hippocampus
with high- and low-frequency electrical stimulation, Mayford et al.
found that different forms of synaptic plasticity can be induced
(Mayford et al. 1995). These differences were attributed to different
protein kinases activated by CaMKII-dependent phosphorylation (Coultrap
and Bayer 2014). Thus, CaMKII phosphorylation acts at different sites in
the postsynaptic membrane, inducing the corresponding forms of synaptic
plasticity.
CaMKII is involved in LTP
In the postsynaptic density, the autophosphorylated CaMKII Thr286
interacts with multiple proteins involved in LTP (Liu et al. 2020).
Zhong, L et al. found that neurogranule protein (Ng) could regulate
synaptic CaM localization and promote CaMKII activation to regulate
synaptic plasticity. (Zhong and Gerges 2019). The amyloid β peptide may
be involved in LTP inhibition by preventing autophosphorylation at
CaMKII Thr286, which reduces synaptic transmission, leading to the loss
of dendritic spines involved in LTP (Opazo et al. 2018). These
experiments confirm that autophosphorylation of CaMKII Thr286 at the
synapse may be involved in LTP. Moreover, CaMKII Thr286
autophosphorylation promotes binding to GluN2B-associated proteins to
maintain LTP. These proteins include α-actinin, synaptic Ras GTPase
activating protein b (SynGAPb), and synapse-associated protein 97
(SAP97). Interference with CaMKII binding to these proteins can reduce
synaptic strength (Sanhueza et al. 2011). Compared to wild-type mice,
depression-like behavior is reduced in mice lacking GluN2B, suggesting
that GluN2B is involved in promoting depression-like behavior (Miller et
al. 2014). During LTP, CaMKII/GluN2B mediation was inhibited by the
CaMKII inhibitor tatCN21, and synaptic strength was impaired at high
inhibitor concentrations, whereas synaptic strength was unchanged at
concentrations that inhibited CaMKII activity (Barcomb et al. 2016).
This suggests that CaMKII/GluN2B interactions maintain synaptic
strength. AMPARs, another type of glutamate receptor closely related to
CaMKII, are also involved in LTP. The antidepressant tianeptine could
effectively restore corticosterone-induced inhibition of LTP and reduce
depressive behavior in mice by reducing the diffusion of AMPARs via the
CaMKII–CACNG2–PSD-95 pathway
(Zhang et al. 2013). Enhanced CaMKIIα-mediated AMPAR synaptic
transmission alleviated chronic stress-induced depression-like behavior
in CUMS mice (Ma et al. 2021). Another study found that enhancement of
the CaMKIIβ-mediated GluA1 pathway in the hippocampus contributes to the
recovery of stress-induced depression-like behaviors (Sakai et al.
2021). These results suggest that CaMKII-mediated glutamate receptors in
the hippocampus are involved in LTP and regulate depressive behavior.
CaMKII regulates LTD-related mechanisms
CaMKII not only regulates LTP but also participates in the development
of LTD by acting on GluA1 Ser567 (Coultrap et al. 2014). Tao et al.
found that CaMKII expression was upregulated in the hippocampus of PSD
rats and that the CaMKII inhibitor KN93 improved depressive behavior in
PSD (Tao et al. 2019). By studying the antidepressant effects of two
cyclic enol ether terpene compounds, Zhang et al. found that combined
treatment with both compounds rapidly inhibited CaMKII phosphorylation
and enhanced BDNF signaling, whereas injection of a CaMKII activator
attenuated its antidepressant effects and BDNF expression (Zhang et al.
2022). Similarly, CaMKII was significantly upregulated in the
hippocampal CA1 region of rats with depressive behavior (Song et al.
2018), suggesting that CaMKII mediates the LTD-promoting role in
depression-related disorders. In the brain, the lateral habenula is a
key region in depression-related disorders (Yang et al. 2018). CaMKII
and AMPAR activity increased in the lateral rein nucleus in animal
models of depression and decreased significantly after antidepressant
treatment, an experiment that demonstrated that CaMKII–AMPAR is a key
signaling pathway in the lateral rein nucleus regulating depression (Li
et al. 2017; Li et al. 2013). CaMKII plays a similar role in the
hippocampus. CaMKII is involved in the P2X2-mediated synaptic inhibition
of AMPARs (Pougnet et al. 2016). CaMKII inhibitors blocked
(RS)-3,5-dihydrophenylglycine (DHPG)-induced hippocampal LTD protein
synthesis in hippocampal slices, indicating that CaMKII is an important
mediator involved in the induction of protein synthesis-dependent LTD.
These findings suggest that CaMKII is involved in the regulation of
synaptic plasticity signified by LTP and LTD (Figure 3).
Cx43 and gap junctions
in the hippocampus
Astrocytic Cx43 is involved in regulating depression-like
behavior
Astrocytes utilize gap-junction proteins such as Cx43 and Cx30 to
modulate synaptic transmission within the brain (Giaume et al. 2010;
Santello et al. 2019a). Studies have revealed that Cx43-deficient mice,
in which the Cx43 protein is removed from astrocytes, exhibit reduced
neuronal excitability, impaired synaptic transmission, and reduced
synaptic plasticity (Hosli et al. 2022). In a related study,
downregulation of the Cx43 gene, which encodes the linker protein Cx43,
was observed in hippocampal astrocytes of depressed and suicidal
patients, providing genetic evidence for the involvement of Cx43 in
depression (Nagy et al. 2017). Cx43 enhances the survival of newly
generated neurons in the adult hippocampus (Liebmann et al. 2013). Huang
et al. discovered that overexpression of Cx30 and inhibition of Cx43 in
the prefrontal cortex and hippocampus of mice experiencing chronic
social defeat stress led to increased and decreased neuronal activity,
respectively, and affected depression-like behavior (Huang et al.
2019a). These results indicate that Cx43 plays a role in regulating
depressive symptoms through the promotion of hippocampal neuronal
activity. However, a recent study reported that Cx43 deficiency leads to
an increase in antidepressant behavior (Quesseveur et al. 2015). The
antidepressant fluoxetine had stronger effects in a mouse model of
depression when administered after Cx43 inactivation compared to its
administration without Cx43 inactivation. Additionally, a single
administration of the Cx43 gap-junction inhibitor carbenoxolone enhanced
the antidepressant effects of fluoxetine (Portal et al. 2020). This
indicates that Cx43 and its gap-junction channels may be involved in the
development of depressive behavior.
Cx43 gap-junction channels regulate hippocampal neuronal
plasticity
Lou et al. discovered that the antidepressant ginsenoside induces
abnormal gap-junction connectivity between hippocampal astrocytes in
rats exposed to corticosterone-induced stress. Additionally, they found
that ginsenosides can reverse the decrease in cx43 expression.
Furthermore, the effect of ginsenosides is blocked by the administration
of the gap-junction blocker carbenoxolone (Lou et al. 2020; Lou et al.
2020; Wang et al. 2021). These studies indicate that the Cx43
gap-junction protein and its pathway in the hippocampus can effectively
alleviate depressive behavior induced by CUMS. Similarly, a decrease in
Cx43 protein expression was observed in PSD rats (Tao et al. 2019).
Hippocampal Cx43 gap junctions play a considerable role in depression.
This is achieved through their involvement in regulating neuronal
plasticity in the hippocampus by allowing the movement of ions,
neurotransmitters, and neuroactive molecules (Chever et al. 2016;
Dallerac et al. 2013; Perea et al. 2009). This regulation is dual in
nature (Pannasch and Rouach 2013; Rouach et al. 2008). In addition to
their direct role in mediating synaptic plasticity, Cx43 gap junctions
can regulate other mechanisms. These gap junctions mediate neuronal
regulation of intracellular Ca2+ levels and the release of neurotrophic
factors in response to glutamate (Chen et al. 2014a; Quesseveur et al.
2013). Recently, xiaoyao powder was found to function as an
antidepressant in a rat model of CUMS-induced depression. It alleviated
neuronal damage in the rat hippocampus by upregulating Cx43 and
modulating the Cx43 pathway, which is linked to the gap-junction channel
in Cx43 (Zhang et al. 2022). In rats with depression-like behavior
induced by CUMS, CUMS exposure leads to the production of
proinflammatory factors. However, Ginsenoside Rg1 alleviated this
behavior and acted as an antidepressant. This effect is achieved by
inhibiting the ubiquitinated degradation of Cx43, which in turn improves
neuroinflammation (Wang et al. 2021). Therefore, the involvement of Cx43
gap-junction channels in the onset of depression is related to the
regulation of neurotrophic factors and neuroinflammation.
Cx43 gap-junction
channels regulate synaptic activity
Glutamate is the primary neurotransmitter of neuronal activity. Within
the hippocampus, Cx43 regulates glutamatergic synaptic transmission and
excitatory neurogenesis, primarily by modulating the level of glutamate
released from presynaptic glutamatergic vesicle pools (Chever et al.
2014). This indicates changes in AMPARs and NMDARs, as well as synaptic
glutamate concentrations, without affecting postsynaptic transmission.
Glutamate release from astrocytes influences the release of presynaptic
neurotransmitters, which is dependent on the regulation of intracellular
calcium ions through astrocytic gap junctions (Huang et al. 2019b).
Likewise, the activity of glutamatergic synapses that rely on sodium
ions is regulated by Cx43 protein channels. Elevated sodium ion levels
within cells can promote sodium-potassium ATPase activity, leading to
increased ATP conversion to lactate and ultimately neurogenesis (Langer
et al. 2012). Thus, sodium propagation plays a crucial role in the
involvement of Cx43 gap-junction proteins in neuronal synaptic
plasticity.
Activation of postsynaptic AMPARs and NMDARs through glutamate release
across the synaptic gap causes an efflux of potassium ions (Sibille et
al. 2014), which leads to cortical spreading depression (Dreier 2011).
Astrocytes can enhance the occurrence of LTP in synapses by absorbing
potassium ions. The complex structure comprising astrocytes and synapses
is referred to as a tripartite synapse (Arizono et al. 2020). Cx43
gap-junction coupling can reduce the activation of extrasynaptically
induced LTD by absorbing potassium ions and glutamate synaptically
released through NMDARs. This enhances LTP in these synapses (Chever et
al. 2014). Overexpression of the linker protein Cx43 can reduce
astrocyte volume, increase glutamate and potassium ion spillover, and
inhibit LTP (Pannasch et al. 2011). The beneficial effects of caloric
restriction on the brain involve decreased Cx43 expression and reduced
extracellular glutamate spillover via gap-junction uncoupling, which
significantly enhances synaptic LTP (Popov et al. 2020). This implies
that the Cx43 gap-junction protein has a dual role in synaptic
plasticity, promoting either LTD or LTP. Previous studies have also
found that the absence of gap-junction proteins can prevent the
redistribution of absorbed glutamate and potassium ions in astrocyte
networks, leading to an increase in extracellular glutamate and
potassium ions and inducing spreading depression (Sykova et al. 1999).
Therefore, we hypothesized that the alteration of extracellular volume
in astrocytes through modulation of Cx43 gap-junction coupling may
regulate synaptic plasticity.
Astrocytes connected via Cx43 gap
junctions play a crucial role in promoting neuronal coordination (Chever
et al. 2016). In adult mice, disruption of astrocyte coupling affects
hippocampal neuronal excitability and LTP, primarily because of changes
in the astrocyte network structure (Hösli et al. 2022; Medina et al.
2016). The impact of astrocyte networks on synaptic neuronal activity
has been extensively reviewed by Pannasch et al. (Pannasch and Rouach
2013) and is not discussed further here. In summary, Cx43 gap junctions
are involved in regulating synaptic plasticity and thus participate in
the modulation of depressive behavior by controlling energy metabolites
during synaptic activity, glutamate release, sodium propagation, and
potassium spillover. The astrocyte network formed by gap-junction
coupling also contributes to this effect (Figure 4).
Neurotransmitter release from Cx43 hemichannels
In addition to gap-junction
channels, Cx43 functions as a hemichannel, which facilitates
communication within cells and may contribute to neuronal synaptic
excitability (Abudara et al. 2018). Jeanson et al. investigated the
effects of seven classes of antidepressants on astrocytes exposed to
lipopolysaccharide (LPS). Their results indicated that antidepressant
treatment inhibited hemichannel activity without affecting Cx43 protein
expression in astrocytes. However, the effect of gap-junction
communication remains unclear (Jeanson et al. 2015). Various
explanations are possible for these findings, including the idea that
Cx43 hemichannels are only involved in glutamatergic neurotransmission
in the LPS model (Orellana et al. 2015a) or that antidepressant drugs
reduce proinflammatory cytokines to control hemichannel activity (Chen
et al. 2014b). Both hypotheses suggest that inhibition of Cx43
hemichannel activity may be a key mechanism by which antidepressants
exert their effects (Abudara et al. 2018).
Astrocytes play a vital role in regulating hippocampal plasticity by
controlling the release of D-serine through Cx43 hemichannels (Santello
et al. 2019b). The release of D-serine induces synaptic LTP in
hippocampal neurons through NMDARs (Yang et al. 2003). However,
excessive neurotransmitter release can have detrimental effects on
neurons. For instance, neurotoxic perfluorooctane sulphonate can damage
hippocampal neurons through the astrocytic Cx43 hemichannel-mediated
D-serine/NMDAR signaling pathway, which can be attenuated by glial cell
uptake of D-serine inhibitors (Wang et al. 2019). Similarly, the
neurotransmitter ATP, released by astrocytes, is crucial for the energy
supply in the brain and plays a crucial role in regulating neuronal
synapses (Winkler et al. 2017). Moreover, the opening of Cx43
hemichannels can lead to the release of large amounts of glutamate,
resulting in an increase in calcium levels and ultimately neuronal
excitotoxicity (Chavez et al. 2019). Recent research demonstrated that
the opening of Cx43 and PanX1 hemichannels in the hippocampus results in
the release of glutamate and ATP, leading to acute or chronic
fasciculation stress in rats (Orellana et al. 2015b). These findings
indicate that increased Cx43 hemichannels are implicated in the
pathogenesis of depression by inducing neuronal damage, primarily
through the release of neurotransmitters. In summary, the regulatory
functions of astrocytes are essential for maintaining neuronal health
and plasticity. Although neurotransmitter release is a critical part of
this function, excessive release can lead to detrimental effects on
neurons. The opening of Cx43 hemichannels has been implicated in the
pathogenesis of depression through its effects on neurotransmitter
release and subsequent neuronal damage.
Serotonin (5-HT) and its receptors
The neurotransmitter 5-HT is involved in depression
In the hippocampus, 5-HT acts as a neurotransmitter and is involved in
regulating synaptic plasticity and neurogenesis (Micheli et al. 2018b;
Palacios-Filardo and Mellor 2019). Aerobic exercise can improve
depression-like behavior in PSD by upregulating 5-HT levels (Tang et al.
2022). Another study also found that both diosgenin and agomelatine
exert their antidepressant effects by increasing 5-HT levels in the
hippocampus of rats (Daszuta et al. 2005; Yang et al. 2017). The
growth-associated protein GAP-43 enhances neurotransmitter release and
neo-synaptic formation, thereby promoting hippocampal synaptic
plasticity (Grasselli and Strata 2013). Resveratrol reduces 5-HT
reuptake, increases 5-HT transmission, and elevates GAP-43 expression in
the hippocampus, resulting in improved depressive behavior in mice (Shen
et al. 2020). This suggests that 5-HT-dependent neurotransmission can
modulate hippocampal synaptic plasticity and promote hippocampal
neuronal activity to improve depressive behavior. Tryptophan hydroxylase
2 (TPH2), the rate-limiting enzyme for 5-HT synthesis, has been found to
increase depressive behavior in Tph2 knockout mice, whereas deletion of
this synthase impairs synaptic plasticity and LTP in the hippocampus
(Gebhardt et al. 2019; Jacobsen et al. 2012). These findings suggest
that 5-HT deficiency may induce depressive behavior by inhibiting
hippocampal LTP. However, a separate study found that neuroplastin 65
(Np65) knockout mice exhibited reduced depression-like behavior, reduced
5-HT levels, and increased the number of neurons (Li et al. 2019).
To investigate the role of 5-HT neurotransmitters in hippocampal
synapses and their relationship with depressive behavior, a clinical
study was conducted on patients with PSD to compare the effects of
asparagine and fluoxetine hydrochloride treatment. The results showed
that antidepressant treatment significantly increased 5-HT and BDNF
levels and improved depressive symptoms (Liang et al. 2019). In
addition, LPS stress induced a decrease in 5-HT and BDNF levels in the
hippocampus of mice, resulting in severer depressive behavior than that
induced by CUMS (Zhao et al. 2019). These findings suggest that these
drugs increase 5-HT and BDNF levels to exert their effects and that 5-HT
may exert its antidepressant effects by modulating BDNF-related
signaling cascades. Overall, the different effects of 5-HT on synaptic
plasticity play a critical role in modulating mood. 5-HT
neurotransmitters affect the action potential frequency of pyramidal
neurons in the hippocampus and modulate GABAergic neurotransmission
(Dale et al. 2016; Homan et al. 2015). They can also enhance
postsynaptic NDMAR activation, promote LTP expression, or inhibit
potassium channels (Palacios-Filardo and Mellor 2019).
5-HT receptors regulate hippocampal neurons
Hippocampal 5-HT receptors regulate synaptic transmission
In the hippocampus, different types of 5-HT receptors play distinct
roles in depressive behavior (Figure 5) (Bombardi et al. 2021). First,
highly expressed 5-HT1A receptors (5-HT1ARs) are believed to be
associated with the onset of depression (Stiedl et al. 2015). Studies
have shown that 5-HT1AR antagonists (NAN-90, pindolol, and WAY100635)
can block the effects of antidepressants such as adenosine (Kaster et
al. 2005), suggesting that the downregulation of 5-HT1ARs in the
hippocampus is critical for the induction of depression. In a mouse
model of cerebral ischemia, a 5-HT1AR agonist reduced depressive
behavior in mice and promoted dendritic remodeling in the hippocampus
(Aguiar et al. 2020). This finding indicates that 5-HT1ARs play an
important role in PSD. Yu et al. found that Shuyu capsules exert their
antidepressant effects by increasing 5-HT1AR protein levels and
activating the 5-HT1AR-mediated cAMP–PKA–CREB signaling pathway in the
hippocampus (Yu et al. 2021). Similarly, another study found that
5-HT1AR mediates PKA–CREB–BDNF signaling in the hippocampus (Shimizu
et al. 2019). Electroacupuncture has been found to reduce 5-HT1A protein
expression in the CA1 region of the hippocampus, enhance LTP, and
improve depression-like behavior (Chen et al. 2020; Han et al. 2018).
Thus, it can be argued that 5-HT1AR-mediated signaling promotes
hippocampal LTP as an important mechanism of action of antidepressant
drugs to improve depressive behavior. In contrast, 5-HT4
receptor-mediated activation in the hippocampus enhances excitatory
transmission at hippocampal synapses (Teixeira et al. 2018),
participates in hippocampal neurogenesis, and increases neuronal
activity. Furthermore, 5-HT4R agonists decrease burst stimulus-induced
LTP, whereas selective 5-HT4R antagonists block this effect (Lecouflet
et al. 2021). By stimulating adenylate cyclase to elevate intracellular
cAMP levels and increase neuronal activity, 5-HT4R exerts its
antidepressant effects by modulating synaptic plasticity and increasing
hippocampal neurogenesis (Hannon and Hoyer 2008). These findings
demonstrate that modulation of synaptic plasticity and promotion of
hippocampal neurogenesis through 5-HT4R has an antidepressant effect.
Hippocampal 5-HT receptors promote depressive behavior
As 5-HT receptors in the hippocampus can facilitate neural activity,
they can also induce depressive behavior by inhibiting neural activity.
A study examining the effects of estrogen on depression revealed that
downregulation of BDNF–TrkB signaling in the hippocampus of mice in a
depression model induced an increase in 5-HT2A receptor activity and
increased their susceptibility to depression (Chhibber et al. 2017b).
This suggests that 5-HT2A plays a facilitatory role in depression, which
is regulated by BDNF signaling. The overactivity of another receptor
subtype, 5-HT2CR, also contributes to the development of depression.
Inhibiting 5-HT2CR-mediated activity of dopaminergic (DA) neurons can
reduce the unwanted effects of selective serotonin reuptake inhibitors
(SSRIs), such as dyskinesia, whereas 5-HT2C receptor antagonists can
enhance the antidepressant and anxiolytic effects of SSRIs and reverse
SSRI-mediated motor deficits (Demireva et al. 2020). Similarly, 5-HT7R
antagonists have been found to exhibit antidepressant effects (Canale et
al. 2016; Kim et al. 2014). Although previous studies have identified a
role for 5-HT7R in ameliorating psychiatric disorders (Costa et al.
2012), recent studies have identified 5-HT7R–MMP-9 signaling as a key
pathway for inducing depression in the hippocampal CA1 region (Bijata et
al. 2022). Overall, studies on 5-HTR have demonstrated its involvement
in hippocampal neurogenesis and its differential regulation of
depressive behavior. The heteroreceptor complex of 5-HTR also plays an
important role in mood regulation. For further details, please see
(Borroto-Escuela et al. 2021).
Dopamine and its receptors
Dopaminergic neurons are involved in depression-related
emotions
Selegiline is a monoamine oxidase (MAO) inhibitor that improves
depressive behavior and has antidepressant effects in patients with
Parkinson’s disease (Kasai et al. 2017). The drug enhances hippocampal
dopaminergic neurotransmission and reduces hippocampal LTP impairment
leading to antidepressant effects, independent of MAO-A inhibition
(Ishikawa et al. 2019). These findings suggest that dopaminergic
neurotransmission in the hippocampus plays a key role in regulating
hippocampal synaptic plasticity independent of 5-HTergic and
noradrenergic pathways. MPTP and 6-OHDA are commonly used to induce
depression and anxiety in Parkinson’s disease mice with affective
disorders (Chia et al. 2020). Increased levels of α-synuclein in the
hippocampus of 6-OHDA-treated mice interfered with dopamine release at
synapses, leading to the impairment of hippocampal plasticity and
neurogenesis, resulting in depression (Schlachetzki et al. 2016). Using
a PSD rat model, Chen et al. found that astragaloside VI can reverse the
decrease in DA levels in the rat hippocampus and exert antidepressant
effects (Chen et al. 2022). The use of antidepressants such as
fluoxetine, acetylcholine, and pioglitazone can reverse hippocampal
neural damage, counteract dopaminergic neuron-induced apoptosis of
neurons in various brain regions, and exert antidepressant effects
(Bonato et al. 2018; Dallé et al. 2020; Singh et al. 2017). Thus,
similar to the 5-HT system, the dopaminergic system is involved in
depression-like behavior by modulating hippocampal neurogenesis (Mallet
et al. 2019). Overall, the antidepressant effects of selegiline may be
attributed to its ability to enhance dopaminergic neurotransmission in
the hippocampus and reduce hippocampal LTP impairment independent of its
MAO-A inhibition. The dopaminergic system plays a crucial role in
regulating hippocampal synaptic plasticity and depression-like behavior,
and DR agonists may have potential as novel antidepressant agents.
Dopamine receptors mediate hippocampal synaptic plasticity
DRs are composed of five distinct G protein-coupled receptors, which are
further divided into D1-like (D1R and D5R) and D2-like (D2R, D3R, and
D4R) subfamilies. These receptor classes differently mediate hippocampal
synaptic plasticity (Figure 5) (Missale et al. 1998). Modafinil is a
novel antidepressant that inhibits excessive autophagy and neuronal cell
death in the hippocampus, thereby affecting synaptic transmission (Cao
et al. 2019). In a mouse model of menopause, D1R and D2R were found to
be involved in the antidepressant effects of modafinil. Furthermore, D1R
and D2R antagonists were found to have opposing effects on
modafinil-induced neurogenesis in the hippocampus, with the former
decreasing and the latter increasing neurogenesis (Yan et al. 2021). D1R
agonists enhance the expression and maintenance of LTP in the
hippocampal CA1 region, whereas D1R antagonists inhibit it (Huang and
Kandel 1995). In contrast, in the dentate gyrus, deletion of the
postsynaptic D2R gene together with D2R pharmacological blockade
impaired NMDAR-mediated LTP and LTD in the hippocampal CA1 region,
whereas its presynaptic deletion had no effect on LTP (Rocchetti et al.
2015). These study findings illustrate the distinct roles of D1- and
D2-like receptors in hippocampal synaptic plasticity.
Various hypotheses have been proposed regarding the distinct roles of
D1- and D2-like receptors in hippocampal synaptic plasticity. First, D1-
and D2-like receptors are differentially distributed in the hippocampus.
D1-like receptor -mediated signaling occurs primarily in granule cells
of the dentate gyrus, whereas D2-like receptor are mainly expressed in
hilar mossy cells or the luminal molecular layer of the dorsal
hippocampus (Charuchinda et al. 1987; Wei et al. 2018). Furthermore,
D1-like receptors positively regulate adenylate cyclase activity, which
leads to increased intracellular cAMP levels. Conversely, D2-like
receptors negatively regulate adenylate cyclase and decrease
intracellular cAMP levels (Klein et al. 2019). Activation of the D4R
subtype, a D2-like receptor, reduces synaptically enhanced AMPAR
currents and CaMKII activity in the hippocampus. Blocking D4R promotes
late hippocampal LTP, which is associated with D2-like receptor
regulation by adenylyl cyclase (Navakkode et al. 2017). In contrast, the
D3R subtype promotes PI3K- and MEK-induced structural plasticity of DA
neurons, which are involved in the antidepressant effects of ketamine
(Cavalleri et al. 2018). Therefore, different subtypes of D2-like
receptors have different modulatory effects on neurons. Finally,
different forms of dopaminergic discharge play a role in the modulation
of these receptors. Tonic firing under low-frequency stimulation can
only activate D2-like receptors with relatively high affinity, whereas
phasic firing under high-frequency stimulation can transiently activate
D1-like receptors with low affinity (Edelmann and Lessmann 2018).
Activation of D1-like receptors has been found to promote enhanced
synaptic glutamatergic transmission of LTP in the CA1 region of the rat
hippocampus (Li et al. 2003). In conclusion, dopamine acts as a
hippocampal neurotransmitter that binds to D1- and D2-like receptors and
regulates synaptic plasticity involved in depression-related mood.
Summary
and future perspectives
In this review, we explored the
role of neurotrophic factors and associated signaling pathways, protein
kinases, gap-junction proteins, neurotransmitters, and their receptors
in the regulation of hippocampal synaptic plasticity in PSD. Alterations
in synaptic plasticity in hippocampal neurons are a crucial mechanism
for generating depressive symptoms, with LTP and LTD being two important
forms of synaptic plasticity. At the molecular level, BDNF and CaMKII in
the hippocampus are involved in both LTP and LTD by binding to
postsynaptic receptors, exerting a bidirectional modulatory effect on
depressive mood. This seemingly contradictory regulation may be due to
their release specificity and different postsynaptic sites (Wang et al.
2022). Postsynaptic event-induced alterations in hippocampal synaptic
plasticity are key mechanisms underlying the pathology of depression. In
addition to regulating postsynaptic activity, the linker protein Cx43 in
the hippocampus and monoamine neurotransmitters act as neuromodulators.
A growing body of research has shown that monoamine neurotransmitters
are released in the synapse, bind to various postsynaptic receptors, and
play different roles in depression. These molecules also play a role in
regulating hippocampal synaptic plasticity, as neurotransmitters in
hippocampal synapses modulate the corresponding postsynaptic receptors.
This explains the current clinical use of multiple monoamine
antidepressants to treat depression via hippocampal synaptic plasticity
mechanisms.
The pathophysiological mechanism of depression involves the
dysregulation of synaptic plasticity, leading to synaptic dysfunction,
resulting in dendritic atrophy, injury, and reduced spine density.
Ultimately, this leads to neuronal cell apoptosis, particularly in brain
regions associated with emotions. Our review of multiple factors linked
to synaptic plasticity in the hippocampus suggests that altered synaptic
plasticity in this region may play a critical role in inducing
depressive behavior. Furthermore, studies on hippocampal gene expression
indicate that the transcription factor neuronal Per-Arnt-Sim domain
protein 4 (NPAS4), which is highly expressed in the hippocampus,
inhibits postsynaptic stress-induced neuronal damage. NPAS4 mRNA
expression is significantly decreased in rats with PSD (Zhang et al.
2014). The hippocampal microRNA (miRNA) genes miRNA-206-3p, miRNA-206-5p
(Guan et al. 2021), and miRNA-124 (Shi et al. 2022) are also implicated
in the development of depression. They achieve this by regulating the
synthesis of the neurotrophic factor BDNF in the hippocampus.
Furthermore, miRNA-26a-3p activates the PTEN–PI3K–Akt signaling
pathway to curb neuronal injury and depression-like behavior (Li et al.
2021). Conversely, overexpression of miRNA-140-5p in the hippocampus of
ischemic mice inhibited neurogenesis. Clinical trials have also shown
that upregulation of this gene could be a possible risk factor for the
development of PSD (Liang et al. 2019). These findings underscore the
critical role of hippocampal neuronal plasticity in the treatment of
depression.
As there is a consensus on the vital role of hippocampal synaptic
plasticity in treating mood-related disorders, future studies on PSD
should include corresponding functional measurements of hippocampal
neurons. Our review revealed that multiple factors in the hippocampus
are involved in the pathological process of depression, highlighting
therapeutic mechanisms for depressive disorders involving hippocampal
synaptic plasticity. These
findings can aid in the development of more effective antidepressant
drugs.
Conflict of Interest
The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a
potential conflict of interest.
Author Contributions
N. S. wrote the manuscript. N. S.
and WQ. C. reviewed the literature. XM. M. and GM.Z. modified the
language. JZ. L. and HY. W. made contributions to the drawing of the
figures and tables and the revision of the manuscript. All authors
contributed to the article and approved the submitted version.
Funding
This work was supported by Focus on Research and Development Program in
Shandong Province (No. 2021LCXZ06), Science and Technology Development
Program of Shandong Traditional Chinese Medicine (2019-0172 and
2019-0057).