INTRODUCTION

The reaction of the hypothalamic–pituitary–adrenal (HPA) axis is the key component of the neuroendocrine response to any significant event (stress). The main constituents of this cascade reaction are the secretion of hypothalamic corticotropin-releasing hormone, which stimulates the release of pituitary adrenocorticotropic hormone (ACTH) evoking in its turn the release of glucocorticoid hormones (GCs) from the adrenal cortex (corticosterone in most rodents, cortisol in humans) [1]. Once in the bloodstream, GCs exert not only peripheral, but also central effects by interacting with their specific receptors in the brain. The diverse range of GC effects on metabolism of nervous tissue has been noted quite long ago and was not surprising to researchers, given the great biochemical and morphological variety of different cell types in the central and peripheral nervous systems [2]. Extensive research conducted over the last decades has provided convincing evidence that GCs are able to regulate the development, survival and death of neurons. At the same time, the paradoxical features of GCs of being critically involved in both neurodegenerative and neuroprotective processes have become evident [3].

GLUCOCORTICOIDS AS KEY NEUROENDOCRINE REGULATORS OF BRAIN PLASTICITY

Normal activity of the HPA axis, which ensures the rhythmic release of GCs, is essential for homeostasis of an organism and surmounting adverse environmental conditions. Acting through the specific intracellular receptors in the brain and at the periphery, GCs regulate behavior, as well as metabolic, cardiovascular, immune, and neuroendocrine activities. In addition to their metabolic effects leading to the production of the required amount of energy, and apart from their immunosuppressive effects, GCs can stimulate the immune system during the circadian elevation of their levels that provides acute-phase defense responses. The GC-mediated negative feedback includes a host of mechanisms leading to limited activation of the HPA axis and preventing the adverse effects of GC overproduction. Circadian and moderate/acute stress-induced elevation of GC levels is required for the survival of neurons, facilitation of glutamatergic neurotransmission, and formation of excitatory synapses, as well as early gene induction [4].

In the nervous system, GCs interact with cellular receptors, glucocorticoid (GR) and mineralocorticoid (MR), which exist in the cytoplasmic/nuclear and membrane forms. Signal transduction via membrane receptors actualizes the rapid non-genomic effects of GCs, specifically, on the excitability and activity of neurons in the hippocampus, hypothalamus, amygdala, and prefrontal cortex, thus affecting cognitive functions, adaptive behavior, and the neuroendocrine system. Cytoplasmic/nuclear receptors are involved in slower and longer changes associated with gene expression. Although GRs are expressed in every cell of the nervous system, their repertoire and expression levels vary extensively, due to which different cell types respond differently to the activation of these receptors. GCs induce structural plasticity in neurons, Schwann cells, microglia, oligodendrocytes and astrocytes, and also affect neurotransmission, specifically, by altering glutamate release and reuptake.

Differential localization of varied GRs in the brain is critically important for the HPA axis-mediated control of brain function. GHs are expressed in most structures and regions of the brain, while MRs are mainly expressed in those brain regions that are crucial for memory and emotion formation, primarily in the structures of the limbic system, specifically, the hippocampus, amygdala, and prefrontal cortex [5]. MRs have high affinity and therefore bind to GCs at low hormone levels, while the affinity of GRs to GC is an order of magnitude lower, hence the activation of these receptors occurs at high GC levels. Rapid GC effects are mainly implemented via a signal transduced by membrane MRs, while slow structural and functional rearrangements of brain cells are predominantly regulated by genomic effects via GRs. Thus, due to GC signal transduction via MRs and GRs, brain cells are able to adequately respond to significant changes and realize rapid and long-term plastic changes. This enables all brain cells, primarily neurons, to respond adequately to a variety of stressors.

Signal transduction via GRs plays a key role in the integration of the response and interaction of key systems (including neurotransmitter, metabolic, neuroimmune, neurotrophin, and others) while maintaining and tuning neuroplasticity. As a result, differentiated reception of GCs in different brain structures and cells controls almost all activities of the nervous system, including learning and memory, regulating them at subcellular, cellular and network levels [1, 6, 7]. In recent years, many mechanisms of GC effects on the synaptic function and synaptic plasticity that underlie cognitive functions and emotions have been deciphered [8]. Speaking simplistically, GCs modulate information encoding in the brain via the MR-mediated signaling mechanisms, while information consolidation and processing via GRs. GCs alter the dynamics of neuronal activity, leading to context-dependent changes, including both excitation and inhibition, and normally, these effects provide and maintain the organism’s responses associated with the task in hand. GCs ensure diversification of available energy sources that can be used to maintain brain activity, however, excessive GC concentrations compromise energy production (ATP) and oxidation in mitochondria. Thus, according to the allostatic load and overload concept, GCs have both adaptive and maladaptive effects [9]. In this regard, HPA axis and GR dysfunction disrupts the adequate response of an organism to significant factors and thus underlies the development of neurological and mental diseases.

Over the past 30 years, there is increasing evidence that the targets of GCs in the brain are the limbic structures, primarily the hippocampus, i.e. the structure with the maximum density of GRs. The cumulative effects of GCs are believed to determine the rate of neuronal loss in the aging hippocampus, so that stress can accelerate hippocampal degeneration during aging. Moreover, under circumstances when the effect of GCs is insufficient to damage neurons, GCs reduce the ability of neurons to survive extreme exposures, such as hypoxia–ischemia, seizures or hypoglycemia [10]. Due to the fact that exactly the hippocampus is a key structure that mediates the implementation of learning and memory, as well as emotions, and considering HPA axis regulation by the hippocampus, GC-induced damage to the hippocampus, including its atrophy, may play an important role in the pathogenesis of a number of neuropsychiatric disorders [11, 12].

BRAIN GLUTAMATERGIC SYSTEM: GLUCOCORTICOID-MEDIATED REGULATION

The universal interneuronal interface, synapse, is a key element of brain plasticity. Glutamate is the most common neurotransmitter in the CNS, with its receptors being present on more than 90% of neurons and 40% of synapses [13]. Currently, more than 20 glutamate receptors (ionotropic that represent an ion channel, and metabotropic, signal transduction through which is mediated by secondary messengers) have been identified in the CNS, with each individual receptor having several subtypes. The functional elements that provide glutamate neurotransmission are pre- and postsynaptic neurons together with glial cells, which form the so-called tripartite synapse [14]. The latter functions via both metabotropic and ionotropic receptors (these receptors and their functions are described in detail in [15]). Glutamate is synthesized from glutamine by glutaminase available in presynaptic neurons, and is then transported to synaptic terminals. In the presynapse, glutamate accumulates in vesicles by vesicular glutamate transporters (VGLUT) 1–3 and is released during depolarization. In doing this, signal transmission is carried out through ionotropic and metabotropic glutamate receptors located in different compartments of the tripartite synapse. The signal transmission is terminated by glutamate uptake from the synaptic cleft by high-performance excitatory amino acid transporters (EAATs), which are predominantly located on astrocytes. In astrocyte, glutamine synthetase converts glutamate into glutamine, which can then enter the extracellular space and presynapse in a process called the glutamate/glutamine cycle. Glutamate receptors and transporters co-operate as critical regulators of the glutamatergic system due to modulation of the signal intensity and extracellular glutamate concentrations. It is the thorough regulation of extracellular glutamate that is crucial for the persistent receptor activation, which can lead to excitotoxicity and neuronal death.

The ionotropic receptors, NMDA (N-methyl D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), colocalized on the postsynaptic membrane, are functionally dependent on each other during membrane depolarization, but interact with glutamate independently. A high density of NMDA receptors, expressed on neurons and astrocytes throughout the brain and particularly in the hippocampus, promotes learning, memory, and synaptic plasticity [16, 17], but receptor hyperactivation leads to neurodegeneration. Such a duality is thought to be due to the subcellular localization of NMDA receptors: their synaptic activation elicits calcium-mediated favorable transcriptional changes, while extrasynaptic activation triggers the signaling pathways that reduce stress tolerance and stimulate neurodegeneration [18]. AMPA receptors are assumed to play an important role in synaptic plasticity by providing the required level of depolarization to unblock NMDA receptors from magnesium block, and indirectly increase calcium influx into a neuron. Ionotropic glutamate receptors mediate rapid neuronal communication, whereas the slower processes are actualized due to signal transduction via metabotropic receptors. Metabotropic receptors of different types, expressed both pre- and postsynaptically, differently modulate glutamatergic transmission, partaking in the implementation of the synaptic plasticity phenomena associated with emotional behavior and cognitive functions [18].

The tuning of glutamatergic transmission is an important mechanism of neuron–neuron communication, since the glutamatergic system plays a crucial role in synaptic stability and plasticity. In this respect, the glutamatergic system of the hippocampus, a key structure involved in the processing of cognitive and emotional information and selectively sensitive to the impact of various stressors, attracts particular attention [1]. The crucial importance of both GCs and glutamate for hippocampal cell viability was noted in the 1990s, when it was shown that hippocampal expression of the genes controlled by GRs is mainly required for the interaction with other transcription factors (e.g., CREB, AP-1), although the binding to hormone-sensitive elements of the GC-specific genes was not excluded either [19].

In recent years, it has been shown that chronic GC excess causes a specific synaptic deficit in the hippocampus, with excitatory glutamatergic synapses, the key components of synaptic transmission, synaptic plasticity and behavioral adaptation, playing a major role therein [20, 21]. Physiological stress activates glutamatergic neurons in the hippocampus, while chronic stress causes a dyshomeostasis of extracellular glutamate. This dyshomeostasis is intensified by excess GCs, leading to changes in cognitive and emotional behavior. At the same time, GC effects on glutamatergic synapses depend on the type and duration of exposure that determines GC levels and dynamics in a region-specific, age- and gender-dependent manner [21].

In our recent review [22], we presented a general diagram of the currently known mechanisms behind the MR- and GR-mediated synaptic effects of GCs in a glutamatergic synapse, based on the results of previously published studies [1, 6, 21, 23–26]. The diagram suggests that the high plasticity of glutamatergic synapses is underlain by a large number of targets of direct or mediated GC influences, the presence of which is exactly what forms a multitude of mechanisms involved in the response of glutamatergic transmission to GCs. This enables an adequate response of an organism in any given situation. The large number of potential mechanisms of signal transduction is determined by the presence of both membrane and cytoplasmic forms of GRs with different affinities (MR and GR) within the same glutamatergic synapse. They provide a wide repertoire of pathways to regulate synaptic plasticity, realized both immediately via the non-genomic mechanisms of synaptic membrane depolarization, and in a delayed manner, due to activation of genomic mechanisms.

According to the proposed scheme, non-genomic mechanisms are mediated by membrane GRs. In a presynapse, GCs bind to high-affinity MRs, thus regulating excitability and the release of glutamatergic vesicles. The frequency of glutamate release is controlled by the G protein-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway. GC binding to postsynaptic membrane GRs suppresses the activation of potassium channels, while their binding to postsynaptic membrane GRs inhibits L- and N-type calcium channels, as well as protein kinase C, reducing thereby calcium influx into the cell. GC binding to postsynaptic membrane GRs inhibits ionotropic NMDA receptors via protein kinase A and enhances hyperpolarization, regulating postsynaptic ionotropic GABAA receptors. The genomic mechanisms of the effect of GCs on glutamatergic transmission are believed to be mainly implemented in the postsynapse and largely by signal transduction via cytoplasmic GRs, although there are data on the involvement of postsynaptic cytoplasmic MRs in the execution of long-term effects of GCs. GCs freely diffuse through the cell membrane and bind in the cytoplasm to MRs and GRs, causing receptor dimerization with the involvement of heat shock proteins. The GR or MR homodimer translocates into the nucleus, where it binds to specific DNA regions of the glucocorticoid response elements (GRE). Cofactors and histone-modifying elements bind to the GRE region, to which the GR homodimer is already bound, resulting in changes (initiation or inhibition) in transcription, gene expression, and protein synthesis, depending on the nature of the factors bound to this region. There have been described, although considered as an exception, genomic effects of GCs implemented via the membrane GR, which under certain conditions can translocate into the nucleus and cause transrepression or trigger ERK1/2-dependent gene transcription. GC-induced genomic effects, most important for glutamatergic transmission, include the modulation of the expression of NMDA and AMPA receptor subunits, as well as glucose metabolism and transport, by changing the activity of its membrane transporters [22].

Along with ionotropic AMPA and NMDA receptors, the function of other glutamate receptors (mGluR1, KA1, GluR6 and GluR7) is also regulated by GCs [22]. The effects of GCs on plasticity mediated by glutamatergic synapses have been demonstrated not only in the hippocampus, but also in other brain structures, crucial for the cognitive function and emotional state, primarily the limbic system. Such data were obtained for the prefrontal and frontal cortices, amygdala and hypothalamus. Importantly, the GC-mediated regulation of glutamatergic transmission may differ dose- and time-dependently in different brain regions and even in the nuclei and regions of the same structure and have opposite effects. At the same time, region-specific effects may concern different subunits of glutamate receptors [22].

Another potential mechanism of the GC-mediated functional control of glutamatergic synapses is the effect of these hormones on the physiology and functioning of astrocytes. Primarily, these effects include the inhibition of glucose transport, reduction in glycogen synthesis and glutamate uptake [27]. In addition, indirect effects of GCs on astrocytes are also possible. GCs reduce serotonin levels in neurons, which affects astrocyte functioning by altering cytokine activity and GABA transport.

The brain-derived neurotrophic factor (BDNF) is a neurotrophin abundantly expressed in the central nervous system. It promotes long-term enhancement of synaptic efficiency associated with specific learning and memory processes. Being one of the key molecules modifying brain plasticity, BDNF modulates glutamatergic transmission through various mechanisms, altering the expression and activity of both ionotropic and metabotropic glutamate receptors, as well as transporters (see review [28]). In a number of studies, there have been demonstrated correlations between the expression/function of BDNF and adrenal hormones (mainly GCs and dehydroepiandrosterone [29]), probably indicative of BDNF-mediated GC-dependent mechanisms of glutamatergic transmission regulation, remaining understudied to date.

Obviously, the direct interaction of GCs with a glutamatergic synapse via GRs does not exhaust the possible mechanisms of interaction between glutamatergic transmission and the HPA axis. There has been established the involvement of excitatory amino acids in the control of ACTH release [30]. Activation of ionotropic glutamate receptors has a stimulating effect on ACTH release, while the role of metabotropic receptors has not yet been studied in detail. Glutamatergic regulation of ACTH release is of clear importance for the stress response. Interestingly, some antidepressants (e.g., tianeptine) which modulate ACTH release, also affect the glutamatergic system of the brain.

HYPERGLUTAMATERGIC CONDITIONS IN BRAIN PATHOLOGIES AND GLUCOCORTICOIDS

In an optimally functioning brain, excitatory and inhibitory signals are regulated and balanced. An excitation–inhibition imbalance disrupts signal transmission and leads to pathological changes in behavior, cognitive and motor functions. An imbalance between the main excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), respectively, leads to disorders at the synaptic level and eventually to neurodegeneration.

Cellular homeostasis of glutamate is of paramount importance for normal brain performance, depending on complex neuron–astrocyte metabolic interactions [31]. Glial cells and, above all, astrocytes as cellular components of glutamatergic synapses, play an important role in maintaining this balance in the norm and pathology [32]. Ever more evidence is accumulating that the pathophysiology of neuropsychiatric disorders, including mood and memory disorders, is associated with the dysfunction and dysregulation of the glutamatergic system, therefore, glutamate homeostasis is crucial for reducing the risk of various neurological and psychiatric diseases. Glutamate dysregulation has been shown both in preclinical models of neurological and psychiatric disorders and in the clinic [33, 34]. Over the recent decades, ample evidence has been obtained that stressful events, acting through GCs and their receptors, evoke a whole complex of changes in glutamatergic signaling in the limbic system of the brain, primarily in the hippocampus and frontal cortex that affect cognitive and emotional processes [35]. These changes concern presynaptic glutamate release, membrane trafficking and degradation of postsynaptic glutamate receptors, spine and cytoskeletal network morphology, as well as epigenetic control of gene expression. The postsynaptic density, a complex subcellular domain implicated in postsynaptic signal transduction, accurate information transmission from one neuron to another, and the implementation of synaptic plasticity, also undergoes modifications. Glutamatergic synaptic dysfunction, which affects postsynaptic density morphology and signaling events, has been described in many neurodegenerative disorders [36].

The term excitotoxicity describes the toxic effects of excitatory neurotransmitters, primarily glutamate. Intense or long-term activation of glutamate receptors in hyperglutamatergic states (i.e., situations accompanied by excessive glutamatergic transmission) triggers a cascade that leads to the development of neurotoxicity and, eventually, to the loss of neuronal functions and cell death. NMDA receptor-mediated excitotoxicity is believed to be a central link in the pathogenesis of many brain diseases, both neurological and psychiatric, based on neurodegenerative processes. The border between a normal physiological function and excitotoxicity is largely controlled by astrocytes, as they can modulate glutamate levels in the synaptic cleft, removing glutamate and providing its subsequent recycling through the glutamate–glutamine cycle [37]. The molecular mechanism of excitotoxicity includes alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, specifically NMDA type. Excitotoxicity can also be considered as a consequence or a cause of other cellular phenomena, including mitochondrial dysfunction and oxidative stress. Calcium influx through extrasynaptic NMDA receptors is associated with calcium overload of neuronal mitochondria. The latter, apart from their role in intracellular ATP production, are involved in calcium homeostasis by acting as a buffering organelle, hence the disruption of mitochondrial calcium homeostasis is associated with neuronal death due to either apoptosis triggering or mitochondrial pore opening [38].

Given the key role of glutamatergic transmission in normal brain functioning, it is no wonder that in almost all cases, when studies have been performed on experimental (brain disease models) or clinical material from patients, there have been revealed glutamatergic system disorders. These disorders have their own specificity depending on the given pathological condition, but are usually associated with changes in the HPA axis, which, as shown above, implements control over glutamatergic transmission. Interestingly, related changes in the brain glutamatergic system and HPA axis activity are also observed under whole-body metabolic changes. For example, a high-fat diet in a rodent experiment revealed elevated levels of corticosterone, aspartate, and glutamate accompanied by NMDA receptor-mediated changes in plasticity, i.e., hippocampal hyperglutamatergic activity was associated with HPA axis dysfunction [39].

The extraordinary capabilities of synaptic plasticity in the hippocampus determine the key role of this brain region in learning and memory, as well as the regulation of emotional state, however, the flip side of this plasticity is a selective sensitivity to GC-mediated injury, specifically due to a high density of GC receptors. It is generally believed that this feature of the hippocampus underlies the emergence and development of cognitive and emotional disorders in aging and neurodegenerative diseases, while progressive neuronal injury due to hyperglutamatergic transmission, in its turn, may be the cause of sustained HPA axis activation, as well as increased expression of vasopressin and corticotorpin-releasing hormone in the hypothalamus [41–43]. Excessive GCs also evoke an increase in the number and a change in the phenotype of microglia, thus promoting a disruption of glutamatergic transmission and potentially aggravating synaptic plasticity and memory impairments [44], while the dysfunction of astrocytes contributes to the development of glutamate excitotoxicity due to glutamate overflow through membrane ionotropic and metabotropic receptors [45].

The interaction between the glutamatergic system and GCs in the pathogenesis of Alzheimer’s disease (AD), the most common and actively studied form of dementia, is of particular interest. The genetic etiology of the vast majority of AD cases is unknown, making the identification of environmental factors involved in the emergence and progression of the disease vitally important. Stress may be a crucial factor promoting the development of AD, as confirmed by a huge number of studies, although the mechanisms underlying this relationship remain incompletely understood [46, 47]. Chronic psychosocial stress is increasingly recognized as a risk factor for sporadic AD. In AD, there have been noted HPA axis dysfunction, while experimental and clinical data indicate that in aging and AD, GC hypersecretion is associated with hippocampal dysfunction [48]. HPA axis dysregulation and elevated basal cortisol levels, which occur in patients with AD, contribute significantly to the pathogenesis of the disease. [49, 50]. The observed GC hypersecretion is mechanistically consistent with a theoretically predicted deterioration of the hippocampal state in AD followed by a decline in the ability of GCs to inhibit the HPA axis. Moderate hypercortisolemia, which already manifests itself at early stages of AD, has been shown to be associated with adrenal hypersensitivity to ACTH [51]. Interestingly, depression is a prodromal and integral part of AD, and can also serve a trigger for incipient AD. The common mechanisms of AD and depression, which also provide comorbidity of these diseases, are an impaired GC secretion, changes in glutamatergic transmission (primarily in the limbic structures), and the development of neuroinflammatory processes [1, 52].

Clinical studies have shown that hyperactivity of the neocortex and hippocampus is characteristic of patients at early stages of AD, progressing toward hypoactivity in later stages of neurodegeneration. The factors that contribute to aberrant neuronal excitability include abnormal intracellular Ca2+ and glutamate levels. Interestingly, hyperexcitability can be a prognostic marker of cognitive dysfunction [53].

Important data on hyperglutamatergic signaling in the hippocampus, as related to AD-like symptoms, have been obtained on APP/PS1 double-transgenic mouse model of AD, carrying mutated forms of the genes encoding the human amyloid precursor protein and presenelin 1. The animals were initially cognitively normal, but had an increased release of glutamate in the hippocampus at the age of 2–4 months. It has been shown that the hyperglutamatergic state in the hippocampus of these animals forms before the accumulation of amyloid plaques. At the age of 6–8 months, early cognitive impairments and the accumulation of amyloid plaques in the brain begin to manifest themselves, while an evident AD-associated neuropathology and severe cognitive impairments emerge at the age of 10–12 months. The administration of the antiglutamatergic drug riluzole (a benzothiazole anticonvulsant that inhibits excessive glutamatergic synaptic transmission by blocking sodium channels) at the age of 2–6 months prevents cognitive decline and restores normal levels of glutamatergic neurotransmission [54]. This is one of the most compelling preclinical evidence that supports a direct association of AD symptoms with a hyperglutamatergic state [55].

The disruption of synaptic plasticity due to functional changes in ionotropic and metabotropic glutamate receptors, as well as the loss of dendrites, occur at early stages of AD [56]. Synaptopathy, the hallmark of AD, is associated with β-amyloid peptide-induced imbalance between synaptic and extrasynaptic NMDA receptors and a reduced number of surface AMPA receptors [57].

A comparison of the data obtained from AD patients with functional studies on animal models of AD shows that at early stages of the disease the accumulation of toxic β-amyloid aggregates, especially dimers and low-molecular-weight oligomers, disrupts glutamate reuptake, leading to its extracellular accumulation and ensuing depolarization of neurons. This brings about neuronal hyperactivation and can promote their injury and degeneration due to glutamate neurotoxicity [58, 59]. Altered mitochondrial glutamate metabolism (intracellular mitochondrial transport and mitochondrial glutamate metabolism) is also closely associated with glutamate imbalance in the brain in AD [60]. Interestingly, changes in glucose and glutamate levels in the brain, which may be a consequence of HPA axis dysfunction, precede the emergence of amyloid plaques in AD [61].

A high cortisol level can exert neurotoxic effects on the hippocampus, contributing to oxidative stress and β-amyloid peptide toxicity. Hippocampal neurons are among the first cells to degenerate in the brain of AD patients. These neurons are vulnerable to oxidative stress, which is an important event in the pathogenesis of AD. GCs intensify oxidative cell death induced by β-amyloid peptide and glutamate [62, 63], thus implementing their deleterious effects on cognitive abilities and further development of AD pathology due to elevated cortisol levels.

Stress and its neurochemical and endocrine mediators have been found to cause changes in glutamatergic synapses and networks, and this, in turn, alters mental status. Ample data obtained on animal models of depression have demonstrated that GC secretion in different models of stress enhances glutamate release and signal transmission in the limbic and cortical brain regions and exerts powerful structural effects, causing dendritic remodeling, reducing the number of synapses, and shrinking the volume of brain structures in a way similar to that in depressed patients [64]. Preclinical studies on depression models showed that GCs have a crucial influence on neuronal excitability and function, especially in the cortical and limbic areas. This influence is realized through glutamatergic synapses due to both non-genomic and the slower, genomic, mechanisms triggered by GCs. Sustained changes in glutamate transmission may play a key role in long-term structural/functional changes associated with mood disorders in patients [65]. In other words, it is now generally recognized that the glutamatergic system is a major mediator of psychiatric pathology, and this reflects a paradigm shift from the monoamine hypothesis of depression to the glutamate-dependent neuroplasticity hypothesis. The latter hypothesis suggests that the volumetric changes, consistently observed in the limbic and cortical regions of depressed patients, are largely due to GC-induced dendritic remodeling and the loss of dendritic spines, and that hyperglutamatergic states play a key role in the induction of non-adaptive cellular effects, which are, in turn, responsible for unfavorable structural changes. The hypothesis finds an indirect proof in the fact that drugs used for the therapy of mood and anxiety disorders (antidepressants) prevent intense glutamate release [66].

Glutamate receptor-mediated enhanced excitatory neurotransmission is usually associated with mesial temporal lobe epilepsy with hippocampal sclerosis [67]. Hyperglutamatergic activity in the hippocampus of such patients is accompanied by elevated GC (cortisol) levels, suggesting both direct and mediated influences of GCs on glutamatergic synapses. For example, in temporal lobe epilepsy, changes in the human hippocampal tryptophan–kinurenine pathway contribute to a hyperglutamatergic state [68], with the activity of this pathway being under GC control [69]. Importantly, glutamatergic system dysfunction in the limbic brain regions (above all, in the hippocampus), associated with HPA axis malfunction, is a key link in epilepsy–depression comorbidity (depressed patients are at higher risk of developing epilepsy and vice versa) [70, 71].

Schizophrenia is another example of brain diseases with a dysfunctional interaction between the HPA axis and glutamatergic system in their pathogenesis. A characteristic feature of schizophrenia is the dysregulation of the HPA axis and inflammatory response system [72]. These abnormalities are thought to be associated with developmental changes in the nervous system in certain brain regions, such as the hippocampus, and may affect mainly the glutamatergic pathways, including due to NMDA receptor dysfunction. Among other proofs, the involvement of glutamatergic dysregulation in the pathophysiology of schizophrenia is confirmed by the ability of NMDA receptor antagonists, such as ketamine, to induce schizophrenia-like behavior. This may be due to their putative neuropathological effects on GABAergic interneurons, which can lead to a hyperglutamatergic state. It is assumed that in schizophrenia, along with NMDA receptors, group II metabotropic glutamate receptors are impaired in some brain regions [73, 74]. In refractory schizophrenia, thalamocortical hyperglutamatergic transmission has been shown to be associated with impaired NMDA and group III metabotropic glutamate receptors [75]. Oxidative stress, which plays a key role in the pathophysiology of schizophrenia, is associated with an excess of free radicals due to the hyperglutamatergic state [76].

Conditions related with brain pathologies caused by alcohol or drug abuse (both addiction and abstinence formation) are also associated with changes in the glutamatergic system and HPA axis functioning. For example, the severity of alcohol withdrawal syndrome accompanied by a hyperglutamatergic state [77], as well as brain injury and cognitive disorders, are associated with the degree of glutamate homeostasis impairment in the brain [78]. GCs play an important role in the formation of ethanol addiction, specifically in increasing glutamatergic synaptic plasticity associated with alcohol consumption by affecting the expression of endogenous polyamines and polyamine-sensitive NMDA receptor subunits [79]. Moreover, interactions between GCs, polyamines and NMDA receptors are important both for the development of ethanol addiction and the emergence of behavioral and neuropathological consequences related with the withdrawal syndrome. The mGluR1 and mGluR5 metabotropic glutamate receptors are also involved in the formation of a hyperglutamatergic state in chronic alcohol consumption [80]. The HPA axis has been shown to play a central role in the formation of cocaine addiction [81], in which the dysregulation of glutamatergic signaling is also observed. For example, cocaine self-administration and withdrawal in rats evoke changes in structural plasticity in the prelimbic cortex, corresponding to an early hypoglutamatergic state, which is then replaced by a hyperglutamatergic state. Interestingly, memantine, which temporarily blocks NMDA receptors and protects neurons from excessive stimulation by excess synaptic glutamate, can attenuate drug addiction [82].

CONCLUSION

The neuroendocrine control implemented by the HPA axis, including due to GC secretion, is fundamentally important for maintaining normal brain function and excitation–inhibition balance. GCs regulate the state of the brain glutamatergic system both directly, via receptors at glutamatergic synapses, and indirectly. The inability of the HPA axis to adequately regulate glutamatergic synaptic plasticity leads to the development of neuropsychiatric diseases, with hyperglutamatergic excitotoxicity states playing a pivotal role in their pathogenesis (Fig. 1).

As exemplified in the previous chapter, the impairment of the GR-mediated control of glutamatergic processes underlies cognitive and emotional disorders, epilepsy, and many other cerebral pathologies, i.e., represents a common basic mechanism for many brain diseases and their comorbidities. A study of the mechanisms of interaction between the HPA axis and glutamatergic system of the brain is of priority translational significance, because the knowledge of these mechanisms can serve as a basis for effective prevention and therapy of both neurological (including neurodegenerative) and psychiatric diseases.

Fig. 1.
figure 1

A general diagram of connections between glucocorticoids (GC) and hyperglutamatergic states in brain pathologies (for explanations see the text).

Full size image

FUNDING

The writing of this review article was implemented within the state assignment.