Symmetric And Asymmetric Synapses Driving Neurodegenerative Disorders Part 2

2.2. Cation–Chloride Cotransporters

Ionotropic GABAergic signaling is primarily supported by the chloride ion gradient across the plasmatic membrane [57]. In mature neurons, the regular GABAA-mediated transmission leads to hyperpolarization by allowing the entry of Cl− ions that increase the intracellular concentration of chloride ([Cl−]i ) (Figure 2) [26,57]. 

Recent studies have found that there is a close relationship between intracellular chloride concentration and memory. Chloride ions are a type of ion that is commonly found in organisms. Its intracellular concentration level can affect neuronal activity and synaptic transmission. Therefore, maintaining an appropriate intracellular chloride concentration is essential for the normal functioning of neurons.

This discovery may be of great significance for understanding the formation and storage mechanism of memory. When learning and memorizing new things, the activity patterns of neurons, especially the efficiency and plasticity of synaptic transmission, will change significantly. If the intracellular chloride concentration is unstable, the occurrence of these changes may be disturbed, leading to problems such as memory impairment.

Therefore, maintaining an appropriate intracellular chloride concentration can promote the normal functioning of neurons and improve memory levels. The results of relevant experimental studies have shown that by regulating chloride ions, cognitive function, and learning and memory abilities can be effectively improved.

In short, there is a close relationship between intracellular chloride concentration and memory. Maintaining an appropriate chloride concentration level can promote the normal functioning of neurons and improve memory levels. This discovery provides us with a new perspective for understanding the formation and storage mechanism of memory and also provides new ideas for the future treatment of neurological diseases such as memory impairment. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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The maintenance of [Cl−] I mainly depends on cation–chloride cotransporters, where Na+ -K+ -2Cl− cotransporters (NKCCs) and K+ -Cl− cotransporters (KCCs) are the most important in the CNS [26,58]. 

The isoform NKCC1 is the only one expressed in the CNS, and its function is to increase the [Cl−]i. In contrast, the isoform KCC2 is the main one responsible for decreasing [Cl−] I in mature neurons [26,58].

It has been well-documented that under some pathological conditions, Cl; can be dysregulated, leading to a depolarization effect mediated by GABAA receptors (Figure 2) [59]This is primarily motivated by a high expression of NKCCl and a low expression ofKCC2, leading to a higher [Cl-]; compared to the extracellular concentration of chloride(Clle) [57,58,60. 

The main cellular cascade involved in the regulation of NKCCl andKCC2 following osmotic stress (low [Cl-];) is the With-No-Lysine (K) (WNK) pathway, which ultimately phosphorylates both NKCC1 and KCC2 with opposite outcomes: NKCC1 is activated whereas KCC2 is inhibited (Figure 2) [61,62]. 

There is compelling evidence showing an increase in neuronal NKCC1 expression immediately after ischemic stroke, an event that contributes to cellular hyperexcitability and cell death [45,60,63–66]. Wang and colleagues [60] have shown that NKCC1 is significantly upregulated in cortical neurons from 3 h to 48 h following focal cerebral ischemia in a rat model. 

Acute pharmacological treatment using bumetanide, an NKCC1 inhibitor drug, revealed a neuroprotective effect by increasing neuronal survival in an in vitro model of stroke [45]. This is in concordance with previous in vivo results showing a reduction in the infarction volume as well as in the ischemic necrotic cell death, especially remarkable when bumetanide was applied preinjury [60,63,67,68]. 

A recent study has shown that the inhibition of NKCC1 from day 7 post-stroke enhanced axonal sprouting from uninjured neurons, resulting in a significant behavioral improvement [66]. As previously shown, stroke triggers the WNK signaling pathway leading to both the activation of NKCC1 and the inhibition of KCC2 via phosphorylation (Figure 2) [62,69]. 

Indeed, the activation of the WNK signaling pathway significantly increased the activity of NKCC1 in cortical and striatal neurons at 6 and 24 h after ischemic stroke in mice [65]. These findings suggest that blocking the activation of the WNK cascade offers a new therapeutic target to improve the outcome following stroke by targeting NKCC1 activation [62,69–72]. 

Contrary to what was seen for NKCC1, the amount of KCC2 at both mRNA and protein levels was downregulated in both rat and mouse models of ischemic stroke [45,64,66,73,74]. Curiously, whereas the KCC2 levels in the plasma membrane are notably reduced 3 h post-ischemia [74], there is a progressive decrease in the levels of total KCC2 given that it is significant on days 1 and 7 post-stroke, but not at 2 h after injury [64]. 

Therefore, a relationship between a maintained expression of KCC2 over time and the long-term survival rate of neurons has been proposed [64], which was recently supported [26,74]. In this study, hippocampal pyramidal neurons had regular levels of KCC2 and did not display damage signals at 6 h post-stroke, but they started to degenerate when KCC2 levels decreased at 48 h after stroke [26]. 

Similarly, an acute blockage of upstream pathways inhibiting KCC2 showed increased neuronal survival following an ischemic incident in mice [74]. Therefore, all this evidence seems to point to the upregulation of KCC2 as a therapeutic target to protect against stroke-induced cell death. 

However, similar to the manipulation of GABA signaling, it is a challenge to decipher the timing between the acute and recovery phases in humans, and hence, to find the correct point at which to change KCC2 expression/activity from increased to decreased to achieve further functional outcome after ischemic stroke [26]. In summary, blocking NKCC1 during the first-hour post-stroke has a remarkable effect on neuronal outcomes by reducing necrotic death. 

Likewise, increasing KCC2 levels displays a beneficial role at least during the acute phase, which raises the interesting question of what would happen if KCC2 was manipulated during the post-acute/chronic phase since higher levels of KCC2 would induce GABA-mediated hyperpolarization leading to a tonic currents-like effect.

3. Alzheimer's Disease

Alzheimer's disease (AD) is clinically characterized as a progressive impairment of memory and cognitive disabilities and is the most common neurodegenerative disorder of the elderly in developed countries. 

The two classical hallmarks of AD are amyloid plaques (extracellular deposits of amyloid-β peptide [Aβ]) and neurofibrillary tangles (NFTs, intracellular filamentous aggregates of tau) [75], the tau pathology being more correlated with neurodegeneration and cognitive impairments than the plaque pathology [76]. 

Although tau has been considered an axonal microtubule-associated protein for many years [77], recent advances have demonstrated that tau plays important roles as a synaptic protein, since changes in its structure or expression affect synaptic plasticity [78–82].

One of the most characteristic symptoms of AD is memory loss [83]. The hippocampus is the main area responsible for the storage, maintenance, and processing of memory, where synaptic plasticity, both LTP and LTD, play an essential role [84]. Herein, we will review the most recent advances in the role of tau at asymmetric synapses in both health and pathological conditions.

3.1. Physiological Tau in Synapses

Although the presence of tau in dendrites and synapses was first thought to occur only during neuronal development or under pathological conditions [85], accumulating evidence is reporting physiological tau at dendrites and postsynapses [78,79,83,86,87], including human brains [88]. 

This location of tau at the somatodendritic domain can be attributed to a local translation [89] or diffusion from the axonal domain [90]. Curiously, there is also a natural translocation of tau from dendrites to the postsynaptic area of asymmetric synapses following LTP [91]. Tau can also be transported from pre- to post-synaptic terminals during neuronal activity in both physiological and pathological conditions [92–94]. 

As previously mentioned, synaptic tau plays different roles besides microtubule dynamics and axonal transport, and it is implicated in the formation, maintenance, and plasticity of synapses as well as in neuronal signaling [86,95–97]. Indeed, tau is a key mediator in the increased spine density driven by brain-derived neurotrophic factor (BDNF) [95]. 

Of relevant physiological importance is the complex that tau forms with both the kinase Fyn and PSD-95, since it can interact with NMDA or AMPA receptors, connecting tau with glutamatergic receptors [86,87,98–100]. Non-phosphorylated tau contributes to the induction of LTP [79,91,101]. Tau undergoes different posttranslational modifications (e.g., phosphorylation or acetylation) at different regulatory sites that affect the function of the protein [102]. 

Glycogen synthase kinase-3 beta (GSK3β) represents one of the most prominent tau kinases, and its function is strongly influenced by patterns of neuronal activity that ultimately induce synaptic plasticity. 

There is a bidirectional pathway whereby physiological GSK3βmediated phosphorylation of tau is needed to induce hippocampal LTD [79], but also LTDinducing stimuli cause GSK3β-mediated phosphorylation of tau in an NMDA receptor-dependent manner [78,79,87]. 

Concretely, tau has a main influence in the NMDA-triggered trafficking of AMPA receptors from synapses by promoting their internalization through the GSK3β/protein interacting with C kinase-1 (PICK1) pathway, which is key for LTD induction [79,103–105]. 

This suggests that only the induction of LTD is associated with the phosphorylation of tau as a downstream target of the GSK3β activity, since tau loss-offunction experiments blocked the induction of LTD but not LTP [78], and GSK3β activity is inhibited during the induction of LTP [106].

3.2. Pathogenic Tau in Synapses

Although tau is necessary in the postsynaptic area, it also acts as a mediator of AD-related synaptic deficits [107]. A recent proteomic study performed in post-mortem tissue from AD patients has revealed that hyperphosphorylated tau directly interacts with proteins that regulate synaptic plasticity [108]. However, these tau-associated synaptic pathologies can be seen even before the formation of NFTs [109,110], and they may be caused by different mechanisms. 

The hyperphosphorylation of tau causes most of the pathological synaptic features seen in AD by increasing the mislocalization of tau from the axonal compartment to the somatodendritic compartment, where it aggregates into oligomers [80,111]. Indeed, AD brains show decreased levels of protein phosphatase 2 (PP2A), a phosphatase implicated in the regulation of AMPARs in the membrane. 

Accordingly, treatments increasing PP2A levels improve the functional outcome in animal models of AD [110]. The increase in hyperphosphorylated tau at dendrites triggers different pathways underlying pathological synapse weakening. For example, it has been reported that there is a specific pruning of asymmetric synapses that is carried out by microglia and induced by hyperphosphorylated tau [80,82]. 

Besides, aberrant tau is critically involved in the turnover and trafficking of NMDA and AMPARs related to the blockade of asymmetric LTP. Tau mediates the lateral movement of NMDARs from synapses to extrasynaptic regions [112], and the hyperphosphorylation of tau at serine 396 has been suggested as an enhancer of this diffusion [79,113]. 

Likewise, different aberrant types of tau decrease the synaptic clustering of both NMDA and AMPA receptors [101,114–117]. Recently, the use of mass spectrometry has allowed the detection of significant decreases in AMPARs and NMDARs located at the PSD fraction in a mouse model of AD [80]. Overall, the induction of LTP at asymmetric synapses is compromised, which ultimately ends in the loss of dendritic spines [118]. 

A new study from Mijalkov et al. [81] has revealed that the loss of dendritic spines in AD individuals occurs at clustered locations and not as a random loss. This fact, added to the reduction in the miniature excitatory postsynaptic currents (mEPSCs) by a postsynaptic decrease in AMPA clustering [114], results in a compromised asymmetric synaptic transmission. 

The main player underlying this hyperactive LTD is again GSK3β, leading to aberrant phosphorylation of tau at the somatodendritic compartment and not at the axon, as thought at first [87,119,120]. A recent and surprising achievement came from the study of Park and coworkers [100] where they described the link between NMDARs, tau/PSD-95 complex, and the neuronal nitric oxide synthase by which hyperphosphorylated tau disrupts this association and leads to endothelial dysfunction. 

This study highlights the complexity behind tauopathies, including AD, where many proteins involved in synapse weakening can also play other roles underlying brain dysfunction. Currently, several epigenomic studies on human AD tissue have revealed that different brain regions affected by tau pathology undergo histone acetyl changes that dysregulate transcription [108,121,122]. 

Following these lines, another new and promising line of investigation points to the relationship between tau aggregates and different RNA molecules, because they can be found together in the cytosol and the nucleus [123]. Large concentrations of tau oligomers have a direct effect on nuclear speckles by altering their composition, organization, and dynamics [123], which opens a new window to study how these tau-driven alterations in RNA processing can impact neurotransmitter receptor dynamics [124]. 

Another mechanism that can cause the misfolding of tau and the subsequent formation of its pathogenic version is the extracellular deposition of Aβ [125]. A striking study from Fani and colleagues [126] has shown that extracellular Aβ oligomers can principally activate extrasynaptic NMDARs but also AMPARs to a lower extent. 

This is carried out by interacting with the lipid membrane that perturbs its mechanical properties, leading to alterations in the mechanosensitivity of receptors (Figure 3) [126]. Since GSK3β kinase can be activated by NMDARs [87], it would not be strange to speculate that this mechanosensitivity-mediated activation of NMDARs can increase GSK3β activity and promote tau hyperphosphorylation (Figure 3). 

GSK3β kinase is also the main factor connecting extracellular Aβ with intracellular tau since the inhibition of GSK3β blocks the increase in phosphorylated tau and therefore prevents the Aβ-induced impairment of LTP [101,127]. Similarly to what is described above, treatments with Aβ oligomers enlarge the dendritic/synaptic location of phosphorylated tau [91], but only when tau is already phosphorylated [128]. 

Other kinases can be also implicated in the aberrant function of tau induced by Aβ. For example, Wu et al. [129] obtained proteomic data suggesting that Aβ activates cyclin-dependent kinase 5 (CDK5) which eventually phosphorylates tau at synaptic sites.

Tau aggregates can recruit and misfold naïve monomeric tau, and so they corrupt healthy tau, spreading the neuronal damage in a process called seeding (Figure 3) [130]. This process has a major relevance since it has been recently discovered that the seeding of synaptic tau starts much before the pathology can be detected in human AD brains [94,131]. 

Interestingly, Dujardin et al. [132] have recently found that a higher seeding activity alarmingly correlates with the rate of clinical AD progression. Moreover, this seeding activity was significantly linked to the phosphorylation at several sites, as shown by mass spectrometry results [132]. 

Two major routes are involved in the dissemination of corrupted tau: (1) traveling between neurons through synapses, and (2) direct translocation to the extracellular space crossing the plasma membrane [94,125,133]. 

Similar to extracellular Aβ oligomers, extracellular tau oligomers trigger seeding and cause the aggregation of monomeric intracellular tau and its posterior mislocation to the somatodendritic compartment [134]. This mechanism is likely involved in the high inhibition of hippocampal LTP seen by Ondrejcak et al. [135]. 

Promisingly, a new pharmacological treatment promotes the microglial-mediated engulfment of extracellular tau oligomers and therefore blocks the spreading of tau pathology within neurons [82]. This achievement opens new lines of investigation addressing the blockage of aberrant tau dissemination once it is released to the extracellular space. 

The upregulation of tau acetylation represents a novel mechanism promoting cognitive decline in AD patients [136]. The acetylation of different lysines may involve distinct pathological mechanisms, such as the accumulation of toxic forms of tau and the enhancement of tau oligomerization, which can have a significant effect on the encoding of hippocampal-dependent memory, among other outcomes [119,136]. 

For example, the acetylation at specific residues, such as K280/K281, has dual and negative outcomes, the loss of microtubule-regulatory function and the gain of aberrant tau aggregation [137]. Related to the ability of tau for extracellular release and subsequent spreading, an interesting study from Caballero and coworkers [138] has revealed that acetylation reduces tau degradation and increases its extracellular location in AD brains.

4. Parkinson's Disease

Parkinson's disease (PD) is a chronic neurodegenerative disease involving the death of the nigral dopaminergic neurons by the combination of different factors, e.g., ambient, genetics, oxidative stress, and/or aging [139–141]. 

The progressive disappearance of DA modulation in the basal ganglia (BG) leads to the characteristic motor symptoms of PD, i.e., akinesia, bradykinesia, resting tremor, and rigidity [141]. Adaptive changes at the synaptic level following DA depletion play a main role in the development of these symptoms. 

The BG is composed of interconnected subcortical regions participating in a large variety of brain functions, such as motor programming and execution, and action selection, among others [142]. 

The mammalian BG comprises the striatum (STR), the external and internal segments of the globus pallidus (GPe and GPi, respectively), the subthalamic nucleus (STN), and the substantia nigra pars compacta and pars reticulate (SNc and SNr, respectively) (Figure 4) [142]. DAergic innervations provided by SNc neurons are essential for controlling BG functions, e.g., modulation of synaptic properties (Figure 4) [143]. 

Therefore, the degeneration of DA neurons leads to synaptic alterations underlying the appearance of PD motor symptoms [143,144]. Both symmetric and asymmetric synapses are present along the different BG nuclei, and they are modulated by DAergic terminals. 

Following DA denervation, both synapses suffer major changes that underlie motor symptoms of PD. Here, we will present the synaptic symmetry in the different BG nuclei and how it changes after the death of DA neurons.

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