Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 + 3259 word(s) 3259 2021-12-08 03:03:49 |
2 update layout and reference Meta information modification 3259 2021-12-10 06:41:06 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Romaus-Sanjurjo, D. Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders. Encyclopedia. Available online: (accessed on 05 December 2023).
Romaus-Sanjurjo D. Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders. Encyclopedia. Available at: Accessed December 05, 2023.
Romaus-Sanjurjo, Daniel. "Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders" Encyclopedia, (accessed December 05, 2023).
Romaus-Sanjurjo, D.(2021, December 09). Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders. In Encyclopedia.
Romaus-Sanjurjo, Daniel. "Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders." Encyclopedia. Web. 09 December, 2021.
Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. The balance between these two systems is critical to maintain a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterwards, it further increases the initial damage. Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson’s disease.

Alzheimer’s disease asymmetric synapses dopamine GABAergic transmission glutamatergic transmission Parkinson's disease stroke symmetric synapses tau

1. Introduction

At the end of the 1950′s, E. G. Gray used electron microscopy to define two different types of synapses in the central nervous system (CNS): asymmetric and symmetric synapses [1]. Based on his achievements, asymmetric (or type I) synapses are defined by a postsynaptic density (PSD), thicker than the presynaptic fraction, whereas symmetric (or type II) synapses present a PSD similar in width to the presynaptic membrane. Subsequently, asymmetric and symmetric synapses were correlated to excitatory or inhibitory signaling, respectively [2]. Although controversial [3], nowadays this terminology is still being used to identify excitatory and inhibitory synapses along CNS.
As mentioned, the PSD is a high-density fraction in the postsynaptic membrane with different roles such as mediating the apposition of pre- and post-synaptic membranes, clustering postsynaptic receptors or coupling the activation of these receptors to cellular signaling [4][5][6]. The PSD in asymmetric synapses is composed of membrane proteins (e.g., α-amino-3-hidroxi-5-metilo-4-isoxazolpropionic receptor [AMPAR], N-methyl-D-aspartate receptor [NMDAR], metabotropic receptors, ion channels and adhesion molecules), scaffold proteins (such as the postsynaptic density protein 95 [PSD-95]), and signaling proteins [6][7]. PSD-95 is the most abundant scaffold protein in postsynapses, where it plays a crucial role in organization by interacting with adhesion molecules, glutamate receptors and signaling proteins through its PDZ domain [8][9]. Accordingly, high levels of PSD-95 are correlated with larger PSDs and enhanced synaptic strength [10]. In contrast, symmetric synapses display a different composition in their PSD, where gamma-aminobutyric acid (GABA) A (GABAA, ionotropic) and GABA B (GABAB, metabotropic) receptors are responsible for mediating inhibitory responses. Interestingly, the number of GABAA receptors at the membrane usually determines the strength of the inhibitory synaptic signaling [11]. Similarly to PSD-95, gephyrin plays an important role in the structure of the inhibitory PSD by clustering GABA receptors and acting as a scaffold protein [12][13]. Both asymmetric and symmetric PSDs are not fixed but constantly changing, reflecting the high plasticity presents in this network. The strength of these synapses can be modified in a bidirectional way by mechanisms such as long-term potentiation (LTP) or long-term depression (LTD), among others [14]. Likewise, modulatory neurotransmitters can also influence and regulate synaptic transmission [15].
LTP and LTD are well-known forms of synaptic plasticity. Most of our knowledge about LTP/LTD came from reports of asymmetric synapses, where NMDA-mediated LTP/LTD is the most studied [14]. In excitatory synapses, LTP is induced only when both pre- and post-synaptic neurons are active, and it is mandatory that the postsynaptic neuron is already depolarized at the moment glutamate binds to NMDARs. This is important because it is needed to reach the highest calcium influx to activate intracellular signaling pathways underlying these synaptic modifications [16]. Contrary to LTP, LTD is generally induced by repeated activation of the presynaptic neuron without postsynaptic activity, that leads to a smaller NMDA-mediated calcium influx and synaptic endocytosis of AMPARs [16][17]. Regarding inhibitory transmission, LTP/LTD mechanisms are also present in inhibitory synapses throughout the brain [18]. Inhibitory LTP or LTD needs the presence of glutamatergic synapses, and therefore, the activation of corresponding glutamate receptors to trigger the underlying cellular mechanisms [19].
Neuromodulators are compounds that modify synaptic transmission by regulating the excitability of both pre- and post-synaptic neurons and the response of receptors to neurotransmitters [20]. Within neuromodulators, dopamine (DA) is one of the most studied because its functions are of such importance that deficits in dopaminergic (DAergic) signaling lead to neurological disorders [15]. Midbrain DAergic neurons represent the main source of DA in the CNS, the substantia nigra pars compacta (SNc) and the ventral tegmental area being two important centers providing significant amount of DA to the basal ganglia (BG) and forebrain [21]. Through the activation of metabotropic receptors (D1-D5), DA can modify the excitability of neurons by regulating the voltage- or ligand-gated channels [15], as well as regulating the function and trafficking of GABA receptors, NMDARs, and AMPARs [22]. In this way, DA is able to affect different synaptic dynamics [23].

2. Ischemic Stroke

Stroke is becoming one of the most common causes of death in developed countries, representing the main cause of long-term disability due to the limited capacity of human brain to repair. Ischemic stroke, the occlusion of a blood vessel leading to a lack of blood flux, has fatal consequences even in short-term blockages and it represents the 85% of total cases in Europe [24][25]. Following the insult, two large areas can be distinguished: the ischemic core, necrotic tissue with irreparable damage; and the peri-infarct, or penumbra, an area containing hypoperfused tissue that is still viable for several hours and can be salvaged by restoration of the blood flow. Over the next few hours to days, this peri-infarct tissue undergoes secondary damage by the activation of the ischemic cascade which eventually leads to neuronal death. The response to the damage varies depending on which cerebral area is affected, the cortex and hippocampus arising as two of the most susceptible areas [26][27]. The timeline of neuronal death differs among these two areas, with cortical neurons displaying a quick death in comparison with hippocampal neurons that show a delayed death occurring 3–5 days following the insult [26]. This exposes the complexity of neuronal connections since every cortical microcircuit responds differently after damage, and the outcome following treatment may not be the same throughout the different cortical layers [28][29].
Two different phases can be distinguished from the onset of an ischemic insult, and each one shows how the imbalance between excitatory and inhibitory signaling can negatively affect neuronal/functional outcome [30]. During the acute phase, under a hypoxic environment, there is a massive presynaptic release of glutamate that overactivates postsynaptic NMDARs. This leads to the entry of large amounts of Ca2+ during the first minutes to hours, which stimulates a variety of cellular processes that ultimately produce irreparable neuronal damage and cell death (Figure 1) [25][30]. Recently, Tanaka et al. [31] reported increased levels of glutamate by using MALDI mass spectrometry imaging in the peri-infarct area of a mouse model. In addition to this, the astrogial-mediated reuptake of glutamate is reduced following injury, further increasing extracellular levels of glutamate [26]. In such a situation, the enhancement of GABA signaling counterbalances the excitatory inputs promoting neuroprotection (Figure 1) [32]. Conversely, during the post-acute/chronic phase, GABA signaling is highly increased and limits neural repair by decreasing neuronal excitability and impairing LTP [33][34]. This occurs simultaneously with a rearrangement of cortical networks underlying neuronal plasticity by enhancing the ability to induce LTP throughout prolonged excitatory signaling during the first week post stroke [33][35][36]. Therefore, treatments blocking GABA signaling during this phase may represent promising therapies to help in the recovery of patients following stroke [28][34][37][38].
Figure 1. Glutamate-mediated excitotoxicity in ischemic stroke. (A) Following ischemic injury, the massive release of glutamate (orange spheres) leads to the entry of large amount of Ca2+, increasing neuronal excitability and activating the Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII phosphorylates both GABAA and GABAB receptors, decreasing their availability; (B) The potentiation of symmetric signaling through agonists (light-blue spheres) of either GABAA or GABAB receptor, or GABA itself (dark-blue spheres), counteracts the glutamate-mediated excitotoxicity by hyperpolarizing the neuron and activating pro-survival second messengers that altogether leads to neuroprotection.
Overall, avoiding the transformation of the penumbra into infarcted tissue is a key target to overcome neuronal damage, and it may improve the outcome of patients after stroke. Besides, it seems pivotal to understand how and when the switch from acute to post-acute/chronic phase occurs in humans in order to tackle the distinct cellular mechanisms underlying neuronal damage over time. Achievements in this field will allow the translation from animal models to human.

2.1. GABA Receptors

GABA signaling through the GABAA receptor is more relevant than the same mediated by GABAB receptors in the pathophysiology of stroke. Therefore, we will focus primarily on GABAA receptors, only citing the most relevant information regarding GABAB receptors.
The different subunits forming ionotropic GABAA receptors determine the properties and location of receptors. These changes in subunit composition are responsible for the synaptic and extrasynaptic location of GABAA receptors, which mediate phasic (synaptic) and tonic (extrasynaptic) inhibition, respectively [32]. During phasic inhibition, GABA released from presynaptic terminals reaches the postsynaptic membrane where it binds to GABAA receptors and triggers an inward chloride current, leading to the hyperpolarization of the neuron. This cellular mechanism represents a transient response defined by a rapid desensitization of the synaptic GABAA receptors and the removal of extrasynaptic GABA by GABA transporters (GATs). On the other hand, tonic inhibition mediates a continuously inhibitory current controlling the neuronal membrane potential and thus its fire potential. Such GABAergic signaling is triggered when extrasynaptic GABAA receptors with high affinity and slow desensitization for GABA respond to either ambient GABA levels outside the synapse or synaptic spillover of GABA. Regarding metabotropic GABAB receptors, they are the mainly regulators of presynaptic glutamate release in excitatory neurons; they also control the activity of postsynaptic glutamate receptors [39].
In the GABAA receptors, trafficking to and from the plasma membrane only occurs at the extrasynaptic space, lateral diffusion being the main mechanism controlling their synaptic pool, and therefore the strength of symmetric signaling [32]. Based on their location, the clustering of GABAA receptors is modulated by gephyrin (synaptic site) or radixin (extrasynaptic site), and both scaffold proteins are positively regulated by phosphorylation, strengthen the clustering at the membrane [32][40][41]. Mele and colleagues [40] suggested that the dephosphorylation of α1 subunit-containing GABAA receptors is directly involved in their internalization, likely by losing the link with gephyrin, following in vitro ischemic damage. Likewise, it has been proposed that the calcium-mediated activation of calpain leads to the cleavage of the gephyrin lattice and subsequent reduction in the synaptic clustering of GABAA receptors in hippocampal neurons from rats under in vitro excitotoxic conditions [42]. Hence, ischemic conditions lead to decreased levels of phosphorylated GABAA receptors, as well as GABAB receptors, suggesting that this is the reason underlying the ischemia-induced endocytosis of receptors. Moreover, this decrease could also explain why GABAB receptors cannot counteract the glutamate-mediated overexcitation [43][44].
Immediately after an ischemic event, large amounts of glutamate contribute to a strong activation of NMDARs that downregulates the expression of both GABAA and GABAB receptors through a phosphorylation process activated by high levels of Ca2+ (Figure 1) [32][43][44][45][46]. Accordingly, phasic GABA signaling is reduced in the first weeks after stroke [28][40]. This situation further increases neuronal depolarization and subsequent cellular damage. Recently, two proteomic studies have revealed increased levels of the GABA aminotransferase GABT, as well as reduced levels of GABA receptors and the excitatory amino acid transporter EAA2, in the infarct core area from postmortem tissue samples of stroke patients [47][48]. These results validate results from animal models by showing overall decreased GABAergic signaling (elevated catabolism of GABA and reduced GABA receptors) and increased glutamatergic signaling (reduced removal from synaptic cleft by EAA2). That is why the enhancement of GABA signaling at this point can exert a neuroprotective role by decreasing the cellular excitability (Figure 1). Indeed, an early study by Costa and coworkers [49] revealed that the coactivation of both GABAA and GABAB receptors promoted neuroprotection in an in vitro model of ischemic stroke. Similarly, the activation of either GABAA or GABAB receptors separately also has pro-survival outcomes. Several studies have reported that the remaining GABAB receptors can be activated between days 1–3 post stroke and this promotes neuroprotection [42][50]. Since the 1990′s, the neuroprotective role of enhancing phasic GABA signaling at the acute phase has been studied throughout pharmacological treatments in both in vitro and in vivo models [39][51]. Likewise, some studies suggest the benefits of enhancing phasic GABA signaling during the chronic phase of stroke in humans [52][53]. It has been reported that the phasic GABA signaling is increased in cortical pyramidal neurons during the chronic phase of stroke [29]. Pharmacological boost of α1 subunit-mediated currents at 3 days post stroke promotes functional recovery by targeting cortical plasticity [29].
Although glutamate is excitotoxic during the acute phase following stroke, it plays a beneficial role during the recovery phase by inducing LTP [33][34]. Indeed, studies in humans have suggested that the stimulation of the penumbra cortex by boosting local excitability as soon as 7 days post stroke improves functional outcome [54]. However, there is an increase in extrasynaptic levels of GABA due to the reduction in the amount of astrogial GABA transporters on day 7 post stroke in mice [28]. This event hyperpolarizes neurons at the penumbra area and negatively modulates the induction of LTP [32][34][55]. Indeed, a recent study using magnetic resonance spectroscopy showed that patients with a low excitatory–inhibitory ratio post stroke had a worse motor outcome [56]. The application of pharmacological treatments negatively targeting either all α subunits or only α5 subunit-mediated tonic GABA currents at 3 days post stroke has shown significant behavioral recovery in mouse models [28][34][37]. Interestingly, it has been reported that there is a possible role of extrasynaptic GABAC receptors, a well-known subclass of GABAA receptors, in these increased tonic currents during post-acute and chronic phases. The application of antagonists targeting GABAC receptors from day 3 post stroke improved the motor function of injured mice [38]. These results together suggest that the time window for the administration of an extrasynaptic GABAA receptor blocker without affecting its initial neuroprotective role is around 3 days after the infarct, at least in mice.
Overall, the potentiation of symmetric signaling immediately after ischemic stroke counteracts the prominent excitatory cellular state promoting neuronal survival. Based on murine models, the acute phase lasts 3 days, and one of the most important questions to be solved is the exact duration of this phase in humans in order to replicate the results from animal models to patients. In contrast, during the postacute and chronic phase, the rise in tonic GABAergic signaling has to be blocked in order to achieve a better functional outcome. Curiously, the potentiation of phasic inhibition is beneficial during the recovery state. It would be interesting to combine pro-GABA drugs during the acute phase and then change them progressively to both prophasic signaling and antitonic currents.

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 increases the intracellular concentration of chloride ([Cl]i) (Figure 2) [26][57]. 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].
Figure 2. Role of NKCC1 and KCC2 cotransporters in the effect of Cl flow through GABAA receptor. (Health). In a normal situation, the expression of both cotransporters leads to a higher [Cl]e compared to the [Cl]i. This results in neuronal hyperpolarization when GABAA receptors are activated; (Injury) After damage, there is an osmotic stress that activates the WNK pathway. This ultimately ends in the phosphorylation of both cotransporters with different outcomes, the expression of KCC2 decreases, whereas the expression of NKCC1 increases; leading to a higher [Cl]i compared to the [Cl]e, which results in depolarizing GABAA receptor-mediated responses.
It has been well-documented that under some pathological conditions, [Cl]i can be dysregulated, leading to a depolarizating effect mediated by GABAA receptors (Figure 2) [59]. This is primarily motivated by a high expression of NKCC1 and a low expression of KCC2, leading to a higher [Cl]i compared to the extracellular concentration of chloride ([Cl]e) [57][58][60]. The main cellular cascade involved in the regulation of NKCC1 and KCC2 following osmotic stress (low [Cl]i) 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][64][65][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 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][70][71][72].
Contrary to what it 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 overtime 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]. In a similar way, an acute blockage of upstream pathways inhibiting KCC2 showed an increased neuronal survival following an ischemic incident in mice [74]. Therefore, all these evidences seem to point at the upregulation of KCC2 as a therapeutic target to provide protection against stroke-induced cell death. However, similar to the manipulation of GABA signaling, it is a challenge to decipher the timing between acute and recovery phase in humans, and hence, to find the correct point at which to change KCC2 expression/activity from increased to decreased in order to achieve further functional outcome after ischemic stroke [26].
In summary, blocking NKCC1 during the first hours post stroke has a remarkable effect on neuronal outcome 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.


  1. Gray, E.G. Axo-somatic and axo-dendritic synapses of the cerebral cortex: An electron microscope study. J. Anat. 1959, 93, 420–433.
  2. Colonnier, M. Synaptic patterns on different cell types in the different laminae of the cat visual cortex. An electron microscope study. Brain Res. 1968, 9, 268–287.
  3. Klemann, C.J.; Roubos, E.W. The gray area between synapse structure and function-Gray’s synapse types I and II revisited. Synapse 2011, 65, 1222–1230.
  4. Siekevitz, P. The postsynaptic density: A possible role in long-lasting effects in the central nervous system. Proc. Natl. Acad. Sci. USA 1985, 82, 3494–3498.
  5. Parato, J.; Bartolini, F. The microtubule cytoskeleton at the synapse. Neurosci. Lett. 2021, 753, 135850.
  6. Moraes, B.J.; Coelho, P.; Fão, L.; Ferreira, I.L.; Rego, A.C. Modified Glutamatergic Postsynapse in Neurodegenerative Disorders. Neuroscience 2021, 454, 116–139.
  7. Smart, T.G.; Paoletti, P. Synaptic neurotransmitter-gated receptors. Cold Spring Harb. Perspect. Biol. 2012, 4, a009662.
  8. Sheng, M.; Kim, E. The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 2011, 3, a005678.
  9. Rodzli, N.A.; Lockhart-Cairns, M.P.; Levy, C.W.; Chipperfield, J.; Bird, L.; Baldock, C.; Prince, S.M. The Dual PDZ Domain from Postsynaptic Density Protein 95 Forms a Scaffold with Peptide Ligand. Biophys J. 2020, 119, 667–689.
  10. Kim, E.; Sheng, M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 2004, 5, 771–781.
  11. Luscher, B.; Fuchs, T.; Kilpatrick, C.L. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 2011, 70, 385–409.
  12. Tyagarajan, S.K.; Fritschy, J.M. Gephyrin: A master regulator of neuronal function? Nat. Rev. Neurosci. 2014, 15, 141–156.
  13. Pizzarelli, R.; Griguoli, M.; Zacchi, P.; Petrini, E.M.; Barberis, A.; Cattaneo, A.; Cherubini, E. Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions. Neuroscience 2020, 439, 125–136.
  14. Abraham, W.C.; Jones, O.D.; Glanzman, D.L. Is plasticity of synapses the mechanism of long-term memory storage? NPJ Sci. Learn. 2019, 4, 9.
  15. Madadi Asl, M.; Vahabie, A.H.; Valizadeh, A. Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling. Basic Clin. Neurosci. 2019, 10, 1–12.
  16. Malenka, R.C. Synaptic plasticity in the hippocampus: LTP and LTD. Cell 1994, 78, 535–538.
  17. Bloodgood, B.L.; Giessel, A.J.; Sabatini, B.L. Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines. PLoS Biol. 2009, 7, e1000190.
  18. Castillo, P.E.; Chiu, C.Q.; Carroll, R.C. Long-term plasticity at inhibitory synapses. Curr. Opin. Neurobiol. 2011, 21, 328–338.
  19. Lüscher, C.; Malenka, R.C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 2012, 4, a005710.
  20. Nadim, F.; Bucher, D. Neuromodulation of neurons and synapses. Curr. Opin. Neurobiol. 2014, 29, 48–56.
  21. Chinta, S.J.; Andersen, J.K. Dopaminergic neurons. Int. J. Biochem. Cell Biol. 2005, 37, 942–946.
  22. Tritsch, N.X.; Sabatini, B.L. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron 2012, 76, 33–50.
  23. Pedrosa, V.; Clopath, C. The Role of Neuromodulators in Cortical Plasticity. A Computational Perspective. Front Synaptic. Neurosci. 2017, 8, 38.
  24. Béjot, Y.; Bailly, H.; Durier, J.; Giroud, M. Epidemiology of stroke in Europe and trends for the 21st century. Presse Med. 2016, 45, e391–e398.
  25. Hay, B.; Yi, S.; Patel, P. Cerebral Ischemia. In Gupta and Gelb’s Essentials of Neuroanesthesia and Neurointensive Care, 2nd ed.; Gupta, A., Gelb, A., Duane, D., Adapa, R., Eds.; Cambridge University Press: Cambridge, UK, 2018; pp. 39–47.
  26. Martín-Aragón Baudel, M.A.; Poole, A.V.; Darlison, M.G. Chloride co-transporters as possible therapeutic targets for stroke. J. Neurochem. 2017, 140, 195–209.
  27. Rahman, A.A.; Amruta, N.; Pinteaux, E.; Bix, G.J. Neurogenesis After Stroke: A Therapeutic Perspective. Transl. Stroke Res. 2021, 12, 1–14.
  28. Clarkson, A.N.; Huang, B.S.; Macisaac, S.E.; Mody, I.; Carmichael, S.T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 2010, 468, 305–309.
  29. Hiu, T.; Farzampour, Z.; Paz, J.T.; Wang, E.H.; Badgely, C.; Olson, A.; Micheva, K.D.; Wang, G.; Lemmens, R.; Tran, K.V.; et al. Enhanced phasic GABA inhibition during the repair phase of stroke: A novel therapeutic target. Brain 2016, 139, 468–480.
  30. Mele, M.; Costa, R.O.; Duarte, C.B. Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders. Front Cell Neurosci. 2019, 13, 77.
  31. Tanaka, E.; Ogawa, Y.; Fujii, R.; Shimonaka, T.; Sato, Y.; Hamazaki, T.; Nagamura-Inoue, T.; Shintaku, H.; Tsuji, M. Metabolomic analysis and mass spectrometry imaging after neonatal stroke and cell therapies in mouse brains. Sci. Rep. 2020, 10, 21881.
  32. Mele, M.; Leal, G.; Duarte, C.B. Role of GABAA R trafficking in the plasticity of inhibitory synapses. J. Neurochem. 2016, 139, 997–1018.
  33. Carmichael, S.T. Brain excitability in stroke: The yin and yang of stroke progression. Arch. Neurol. 2012, 69, 161–167.
  34. Alia, C.; Spalletti, C.; Lai, S.; Panarese, A.; Micera, S.; Caleo, M. Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci. Rep. 2016, 6, 37823.
  35. Hagemann, G.; Redecker, C.; Neumann-Haefelin, T.; Freund, H.J.; Witte, O.W. Increased long-term potentiation in the surround of experimentally induced focal cortical infarction. Ann. Neurol. 1998, 44, 255–258.
  36. Cramer, S.C. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann. Neurol. 2008, 63, 272–287.
  37. Wang, Y.C.; Dzyubenko, E.; Sanchez-Mendoza, E.H.; Sardari, M.; Silva de Carvalho, T.; Doeppner, T.R.; Kaltwasser, B.; Machado, P.; Kleinschnitz, C.; Bassetti, C.L.; et al. Postacute Delivery of GABAA α5 Antagonist Promotes Postischemic Neurological Recovery and Peri-infarct Brain Remodeling. Stroke 2018, 49, 2495–2503.
  38. van Nieuwenhuijzen, P.S.; Parker, K.; Liao, V.; Houlton, J.; Kim, H.L.; Johnston, G.A.R.; Hanrahan, J.R.; Chebib, M.; Clarkson, A.N. Targeting GABAC Receptors Improves Post-Stroke Motor Recovery. Brain Sci. 2021, 11, 315.
  39. Chalifoux, J.R.; Carter, A.G. GABAB receptor modulation of synaptic function. Curr. Opin. Neurobiol. 2011, 21, 339–344.
  40. Mele, M.; Ribeiro, L.; Inácio, A.R.; Wieloch, T.; Duarte, C.B. GABA(A) receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia. Neurobiol. Dis. 2014, 65, 220–232.
  41. Hausrat, T.J.; Muhia, M.; Gerrow, K.; Thomas, P.; Hirdes, W.; Tsukita, S.; Heisler, F.F.; Herich, L.; Dubroqua, S.; Breiden, P.; et al. Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory. Nat. Commun. 2015, 6, 6872.
  42. Costa, J.T.; Mele, M.; Baptista, M.S.; Gomes, J.R.; Ruscher, K.; Nobre, R.J.; de Almeida, L.P.; Wieloch, T.; Duarte, C.B. Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death. Mol. Neurobiol. 2016, 53, 3513–3527.
  43. Benke, D.; Balakrishnan, K.; Zemoura, K. Regulation of cell surface GABA(B) receptors: Contribution to synaptic plasticity in neurological diseases. Adv. Pharm. 2015, 73, 41–70.
  44. Huang, L.; Li, Q.; Wen, R.; Yu, Z.; Li, N.; Ma, L.; Feng, W. Rho-kinase inhibitor prevents acute injury against transient focal cerebral ischemia by enhancing the expression and function of GABA receptors in rats. Eur. J. Pharm. 2017, 797, 134–142.
  45. Zagrean, A.M.; Grigoras, I.F.; Iesanu, M.I.; Ionescu, R.B.; Chitimus, D.M.; Haret, R.M.; Ianosi, B.; Ceanga, M.; Zagrean, L. Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation. Brain. Sci. 2019, 9, 360.
  46. Zemoura, K.; Balakrishnan, K.; Grampp, T.; Benke, D. Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) β-Dependent Phosphorylation of GABAB1 Triggers Lysosomal Degradation of GABAB Receptors via Mind Bomb-2 (MIB2)-Mediated Lys-63-Linked Ubiquitination. Mol. Neurobiol. 2019, 56, 1293–1309.
  47. García-Berrocoso, T.; Llombart, V.; Colàs-Campàs, L.; Hainard, A.; Licker, V.; Penalba, A.; Ramiro, L.; Simats, A.; Bustamante, A.; Martínez-Saez, E.; et al. Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia. Mol. Cell. Proteom. 2018, 17, 175–189.
  48. Ramiro, L.; García-Berrocoso, T.; Briansó, F.; Goicoechea, L.; Simats, A.; Llombart, V.; Gonzalo, R.; Hainard, A.; Martínez-Saez, E.; Canals, F.; et al. Integrative Multi-omics Analysis to Characterize Human Brain Ischemia. Mol. Neurobiol. 2021, 58, 4107–4121.
  49. Costa, C.; Leone, G.; Saulle, E.; Pisani, F.; Bernardi, G.; Calabresi, P. Coactivation of GABA(A) and GABA(B) receptor results in neuroprotection during in vitro ischemia. Stroke 2004, 35, 596–600.
  50. Yuan, Y.J.; Ye, Z.; Yu, H.; Chen, Y.; Wang, Y.W.; Zhao, J.H.; Sun, J.F.; Xu, L.M. Shrm4 contributes to autophagy inhibition and neuroprotection following ischemic stroke by mediating GABAB receptor activation. FASEB J. 2020, 34, 15837–15848.
  51. Lyden, P.D.; Hedges, B. Protective effect of synaptic inhibition during cerebral ischemia in rats and rabbits. Stroke 1992, 23, 1463–1470.
  52. Shames, J.L.; Ring, H. Transient reversal of anoxic brain injury-related minimally conscious state after zolpidem administration: A case report. Arch. Phys. Med. Rehabil. 2008, 89, 386–388.
  53. Hall, S.D.; Yamawaki, N.; Fisher, A.E.; Clauss, R.P.; Woodhall, G.L.; Stanford, I.M. GABA(A) alpha-1 subunit mediated desynchronization of elevated low frequency oscillations alleviates specific dysfunction in stroke--a case report. Clin. Neurophysiol. 2010, 121, 549–555.
  54. Hummel, F.C.; Cohen, L.G. Non-invasive brain stimulation: A new strategy to improve neurorehabilitation after stroke? Lancet Neurol. 2006, 5, 708–712.
  55. Kokinovic, B.; Medini, P. Loss of GABAB -mediated interhemispheric synaptic inhibition in stroke periphery. J. Physiol. 2018, 596, 1949–1964.
  56. Cirillo, J.; Mooney, R.A.; Ackerley, S.J.; Barber, P.A.; Borges, V.M.; Clarkson, A.N.; Mangold, C.; Ren, A.; Smith, M.C.; Stinear, C.M.; et al. Neurochemical balance and inhibition at the subacute stage after stroke. J. Neurophysiol. 2020, 123, 1775–1790.
  57. Schulte, J.T.; Wierenga, C.J.; Bruining, H. Chloride transporters and GABA polarity in developmental, neurological and psychiatric conditions. Neurosci. Biobehav. Rev. 2018, 90, 260–271.
  58. Romaus-Sanjurjo, D.; Rodicio, M.C.; Barreiro-Iglesias, A. Gamma-aminobutyric acid (GABA) promotes recovery from spinal cord injury in lampreys: Role of GABA receptors and perspective on the translation to mammals. Neural Regen. Res. 2019, 14, 1695–1696.
  59. Ben-Ari, Y. NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci. 2017, 40, 536–554.
  60. Wang, G.; Huang, H.; He, Y.; Ruan, L.; Huang, J. Bumetanide protects focal cerebral ischemia-reperfusion injury in rat. Int. J. Clin. Exp. Pathol. 2014, 7, 1487–1494.
  61. Zhang, J.; Gao, G.; Begum, G.; Wang, J.; Khanna, A.R.; Shmukler, B.E.; Daubner, G.M.; de Los Heros, P.; Davies, P.; Varghese, J.; et al. Functional kinomics establishes a critical node of volume-sensitive cation-Cl− cotransporter regulation in the mammalian brain. Sci. Rep. 2016, 6, 35986.
  62. Josiah, S.S.; Meor Azlan, N.F.; Zhang, J. Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. Int. J. Mol. Sci. 2021, 22, 1232.
  63. Yan, Y.; Dempsey, R.J.; Flemmer, A.; Forbush, B.; Sun, D. Inhibition of Na(+)-K(+)-Cl(-) cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res. 2003, 961, 22–31.
  64. Jaenisch, N.; Witte, O.W.; Frahm, C. Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia. Stroke 2010, 41, e151–e159.
  65. Begum, G.; Yuan, H.; Kahle, K.T.; Li, L.; Wang, S.; Shi, Y.; Shmukler, B.E.; Yang, S.S.; Lin, S.H.; Alper, S.L.; et al. Inhibition of WNK3 Kinase Signaling Reduces Brain Damage and Accelerates Neurological Recovery After Stroke. Stroke 2015, 46, 1956–1965.
  66. Mu, X.P.; Wang, H.B.; Cheng, X.; Yang, L.; Sun, X.Y.; Qu, H.L.; Zhao, S.S.; Zhou, Z.K.; Liu, T.T.; Xiao, T.; et al. Inhibition of Nkcc1 promotes axonal growth and motor recovery in ischemic rats. Neuroscience 2017, 365, 83–93.
  67. Glykys, J.; Dzhala, V.; Egawa, K.; Kahle, K.T.; Delpire, E.; Staley, K. Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential. Trends Neurosci. 2017, 40, 276–294.
  68. Xu, W.; Mu, X.; Wang, H.; Song, C.; Ma, W.; Jolkkonen, J.; Zhao, C. Chloride Co-transporter NKCC1 Inhibitor Bumetanide Enhances Neurogenesis and Behavioral Recovery in Rats After Experimental Stroke. Mol. Neurobiol. 2017, 54, 2406–2414.
  69. Huang, H.; Song, S.; Banerjee, S.; Jiang, T.; Zhang, J.; Kahle, K.T.; Sun, D.; Zhang, Z. The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases. Aging Dis. 2019, 10, 626–636.
  70. Bhuiyan, M.I.H.; Song, S.; Yuan, H.; Begum, G.; Kofler, J.; Kahle, K.T.; Yang, S.S.; Lin, S.H.; Alper, S.L.; Subramanya, A.R.; et al. WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats. J. Cereb. Blood Flow Metab. 2017, 37, 2780–2794.
  71. Shekarabi, M.; Zhang, J.; Khanna, A.R.; Ellison, D.H.; Delpire, E.; Kahle, K.T. WNK Kinase Signaling in Ion Homeostasis and Human Disease. Cell Metab. 2017, 25, 285–299.
  72. Zhang, J.; Bhuiyan, M.I.H.; Zhang, T.; Karimy, J.K.; Wu, Z.; Fiesler, V.M.; Zhang, J.; Huang, H.; Hasan, M.N.; Skrzypiec, A.E.; et al. Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a. Nat. Commun. 2020, 11, 78.
  73. Pin-Barre, C.; Constans, A.; Brisswalter, J.; Pellegrino, C.; Laurin, J. Effects of High-Versus Moderate-Intensity Training on Neuroplasticity and Functional Recovery After Focal Ischemia. Stroke 2017, 48, 2855–2864.
  74. Khirug, S.; Soni, S.; Saez Garcia, M.; Tessier, M.; Zhou, L.; Kulesskaya, N.; Rauvala, H.; Lindholm, D.; Ludwig, A.; Molinari, F.; et al. Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression. Mol. Neurobiol. 2021, 58, 1145–1161.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 826
Revisions: 2 times (View History)
Update Date: 10 Dec 2021