PubMed: 30061532

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders.
International journal of molecular sciences
Busceti CL | Fornai F | Frati A | Limanaqi F | Ryskalin L

Evidence 127161fbc6

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents

Evidence 3bf90caf44

In fact, lithium is able to delay METH-induced sensitization, while being a powerful treatment in schizophrenia

Evidence 40db20552f

Likewise, administration of either D1R agonists or METH enhances Akt activity and over-activates mTOR signaling

Evidence e06cf2c0c3

These pieces of evidence corroborate findings showing that several autophagy inducers, such as lithium, rapamycin, and Food and Drug Administration (FDA) approved antipsychotic drugs are effective to treat psychosis including schizophrenia

Evidence 26f285ec0a

Again, rapamycin and rapalogs protect against toxicity produced by a number of misfolded proteins encompassing alpha synuclein, TDP43, and hyperphosphorylated tau

Evidence b6999c2e8b

Beyond METH, redox-related changes that result from an imbalance between reactive oxygen species (ROS) production and ROS clearance are implicated in schizophrenia

Evidence c8a4cbea41

Both administration of amphetamines and stimulation of D1R induce a significant increase of CDK5 gene expression and protein levels, which, at molecular level, associates with increased dendritic spine density and hyper-phosphorylation of the cytoskeletal tau protein

Evidence e0e3039fc5

In contrast, chlorpromazine, which is a typical antipsychotic agent, induces autophagy by inhibiting the Akt/mTOR pathway

Evidence fdfc0950e5

Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines

Evidence ff038edf21

Similar to pimozide, clozapine activates the autophagy process via the AMPK–ULK1–Beclin1 pathway, as evidenced by increased levels of autophagy markers (i.e., LC3-II and Atg5–Atg12 conjugate); increased phosphorylation of AMPK and its downstream substrates, namely ULK1 and beclin1; and an increased number of autophagosomes in the frontal cortex in clozapine-treated rats

Evidence 1cfd9fd3d1

Chronic clozapine treatment (20 mg/kg/day) reduces Abeta deposition

Evidence 8d38cc4e3f

Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia

Evidence 6a5c97bfbd

In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent

Evidence eff1ffcc96

In fact, METH produces a massive increase of endogenous intra-cytosolic DA levels by inhibiting and reverting the direction of the vesicular monoamine transporter type 2 (VMAT-2), thus disrupting the physiological storage of DA

Evidence b83071dc5e

It is worth mentioning that freely diffusible intra-cytosolic DA can readily undergo auto-oxidation and produce a cascade of oxidative-related damage, which is bound to the neurotoxic effects of high doses of METH

Evidence 05d7993f6a

In line with this, experimental models of DISC1 deficiency treated with METH show a significant potentiation of DA release, along with increased expression of D1R in the ventral striatum when compared with controls

Evidence 0bc1490ed5

For instance, haloperidol occludes huntingtin aggregation

Evidence 0accd326eb

As detailed in the following paragraph, METH exerts disruptive effects on DA neurotransmission, which translate into abnormal stimulation of post-synaptic DA receptors, mainly D1-type DA receptors (D1R), thus leading to non-canonical signaling cascades sustaining behavioral alterations that overlap with schizophrenia-like symptoms (i.e., visual and auditory hallucinations and delusions)

Evidence e3082578a9

These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2)

Evidence 3df0e401c0

In addition, several susceptibility genes for schizophrenia (e.g., DISC1, NRG1/ErbB4, and CRMP2), which are involved in either pre-synaptic DA release or post-synaptic D1R-related cascades, are similarly dysregulated by METH. Interestingly, they all converge on mTOR signaling (see Section 6, Table 1).

Evidence 650700ae86

In humans, the sensitizing effects of prolonged chronic METH intake are considered a major determinant to the occurrence and relapse of psychoses, which mirror those occurring in schizophrenic patients

Evidence f18ff95384

Such an abnormal DA release produces peaks of extracellular DA, which cannot be taken up within nerve terminals, because METH inhibits and reverts the direction of the dopamine transporter (DAT).

Evidence 573735ff42

In line with this, recent studies suggest that DAT expression is significantly reduced in the midbrain of postmortem schizophrenic samples [150], which is reminiscent of the METH-addicted brain [151,152].

Evidence 388727cce2

A reduction in VMAT-2 gene expression and protein levels in DA neurons occurs in both METH models and schizophrenic patients, marking quite impressively the overlap between these disorders

Evidence 33bb0ba41b

Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers.

Evidence 85f585abf3

For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD

Evidence 147ada64cf

In particular, pimozide provides an mTOR-independent autophagy induction, because it directly activates AMPK1, which in turn promotes autophagy through the phosphorylation of ULK1

Evidence c98c82b084

This is further supported by mounting evidence obtained in rodent models, which demonstrate that rapamycin normalizes impaired social interactions and reverses behavioral defects

Evidence bf613de225

In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137].

Evidence 07aab4f4cb

Likewise, rapamycin was found to be beneficial for ameliorating psychotic symptoms

Evidence 1ea18f8112

Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy

Evidence 4c02244934

In particular, CRMP2 is a cytosolic protein enriched in the CNS, which has been implicated in microtubule stabilization, and thus in the regulation of cytoskeletal dynamics and vesicle trafficking

Evidence 406336532b

This gene encodes for the DISC1 ubiquitous protein, which is implicated in neurogenesis, neuronal migration, axon/dendrite, and synapse formation

Evidence 9dabf84fb6

The biological implication behind an impairment of microtubule dynamics is confirmed in post-mortem schizophrenic brain samples, as well as in mouse models of schizophrenia, where mTOR-dependent autophagy dysfunction is accompanied by an altered gene expression and protein levels of the microtubule-associated protein 6 (MAP6)

Evidence e3e289495c

In schizophrenia, a progressive synaptic disorder is likely to promote neurodegeneration

Evidence 0170523f87

On the other hand, chronic treatment with an eight-amino-acid peptide snippet from ADNP (NAP), also known as davunetide, restored both Beclin1 and ADNP mRNA levels along with ADNP-LC3 interaction, thus providing neuroprotection while ameliorating schizophrenic-like behavioral and cognitive deficits in Map6+/- mice

Evidence 6527f07b5c

This gene is located on chromosome 8p21 and it encodes the cytosolic microtubule-associated protein CRMP2 (collapsin response mediator protein-2), which is highly expressed in the CNS and plays a role in axonal growth

Evidence 06b1507c52

In addition, cytoskeletal derangement appears as a prominent feature of the ultrastructural pathology of schizophrenia

Evidence f73e8737e5

Alterations in MAP2 immunoreactivity within the subiculum, entorhinal cortex, hippocampus, and prefrontal cortex have been suggested as the primary array of cytoskeletal abnormalities, which in turn result in impaired neurotransmission observed in schizophrenia

Evidence a6239bfb59

Remarkably, the marked reduction of p35 levels in schizophrenic brains, which mirrors enhanced CDK5 activity [247], suggests a role for CDK5-CRMP2-dependent alterations of cytoskeleton architecture and psychiatric behavior

Evidence c3578b82df

Remarkably, DISC1 plays a key role in DA neurotransmission

Evidence baaa20c5d8

Cytoskeleton organization and dynamics depend on the fine control of microtubule assembly, which relies on the interaction of microtubules with a specific class of proteins known as microtubule-associated protein (MAP).

Evidence 7a5e8479e1

Again, an impaired Akt signaling, achieved by neuronal deletion of rictor, a key regulatory subunit of mTORC2, contributes to schizophrenia-like phenotypes in rictor-null (KO) mice

Evidence 632705c7e9

Moreover, it has been demonstrated that NRG1 also regulates DISC1 expression [230], thus further worsening the aberrancy of the Akt–mTOR pathway and the pathogenesis of schizophrenia and related behaviors.

Evidence 21e544c7e7

Remarkably, further investigation on the autophagy pathway revealed that all these misfolded proteins are autophagy substrates depending on mTOR activity

Evidence a1a873a967

Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation

Evidence c392ae39bd

The relevance of autophagy for sustaining these mTOR-induced effects is confirmed by drugs inducing autophagy independently of mTOR activation

Evidence ea8d6b2e00

This confirms our previous studies showing that both genetic and pharmacological autophagy inhibition worsen the effects of METH administration

Evidence 1c65296101

Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia

Evidence 2c7059f9e4

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms

Evidence a3392bebd8

Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients

Evidence fac833071f

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls

Evidence a23344d9ff

Preliminary in vitro studies demonstrated that two proteins, namely DISC1 and dysbindin-1, which are encoded by two susceptibility genes for schizophrenia, can form insoluble protein aggregates that are reminiscent of those occurring in neurodegenerative disorders

Evidence 51d656d6b1

Intriguingly, the interactome analysis of both DISC1, dysbindin-1, and CRMP2, which is another susceptibility gene for schizophrenia, revealed common protein interactions with microtubules, actin cytoskeleton, and proteins involved in intracellular transport

Evidence 4cdb152bb0

In particular, DISC1 acts by blocking KIAA1212, an Akt-binding partner, which directly interacts with Akt and strengthens the activation of this kinase, which represents a major mediator of the mTOR pathway.

Evidence 1ff77b9fe1

In line with this, the dendritic spine-regulating activity of CRMP2 is under the control of the cyclin-dependent kinase 5 (CDK5)

Evidence b6942397da

Therefore, the binding between DISC1 and KIAA1212 prevents KIAA1212-dependent Akt activation (Figure 3).

Evidence c9a8f02969

The binding between ErbB4 and PI3K activates this latter kinase, which in turn can phosphorylate and activate its downstream target Akt

Evidence 6c6436a474

Furthermore, genetic linkage and association studies led to the identification of two additional susceptibility factors related to schizophrenia, such as neuregulin-1 (NRG1) and its receptor ErbB4

Evidence ed81fd8a9d

ADNP is an essential protein for brain development and it has been shown to physically interact with a key protein in autophagosome biogenesis and maturation, namely LC3

Evidence c9e64c5cca

This decreases Akt activity, which in turn dampens mTOR signaling

Evidence 0f505a01ea

In particular, NRG1, which is mostly involved in regulating neurodevelopment and neurotransmission, acts by binding ErbB4, a type I transmembrane receptor tyrosine kinase belonging to the family of ErbB proteins, which contain a binding site for PI3K kinase, an AKT upstream effector, in the C-terminal cytoplasmic tail (CYT)

Evidence 02da67aded

Noteworthy, NRG1/ErbB4 signaling plays a key role in DA-related behaviors by increasing DA release within the hippocampus, striatum, and prefrontal cortex

Evidence e756b731aa

This is the case of the disrupted in schizophrenia 1 (DISC1) gene, a schizophrenia-related gene, originally discovered in a large Scottish family with a high incidence of psychiatric symptoms

Evidence bad164171e

Another identified susceptibility gene for schizophrenia is the dihydropyrimidinase-like 2 (DPYSL2) gene

Evidence 6049f7150a

In detail, the activation of CDK5 by D1R occurs via proteolysis of p35, the binding partner of CDK5

Evidence 6fab3a2b38

In addition, these findings strongly suggest that DISC1 alterations may increase the risk of schizophrenia by dysregulating DA release

Evidence 5bf647b6ac

Therefore, disruption of DISC1 activity, due to genetic rearrangements (i.e., balanced (1;11) (q42;q14) chromosomal translocation) or missense mutations, produces schizophrenic-like behavior, which is bound to enhanced Akt activity, over-activation of mTOR signaling, and depressed autophagy

Evidence 10e76c6f9f

Increased activity of D1R is considered as a major determinant of neuropsychiatric alterations occurring in both METH models/abusers and in schizophrenia

Evidence 836ef1ed77

This is key, because abnormal stimulation of D1R and subsequent signaling cascades were recently shown to produce an over-activation of mTOR and inhibition of the autophagy machinery

Evidence b1dcaad30f

Among various identified MAPs, microtubule-associated protein 2 (MAP2), which belongs to the MAP2/Tau family, is enriched in the brain and especially in dendrites, where it contributes to microtubule stabilization and overall dendritic architecture.

Evidence ba5e7a846b

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia

Evidence afced2ba33

For instance, an increased mTOR activity correlates with accumulation of Abeta and hyperphosphorylated tau in AD brains

Evidence f40cf8a8d5

On the other hand, some evidence indicates that suppressing mTOR activity ameliorates AD cognitive defects by decreasing Abeta and tau pathology

Evidence 16051e80de

In addition, the occurrence of alpha synuclein gene (SNCA) polymorphisms is associated with human METH psychosis [166].

Evidence 1f9c310843

Remarkably, a very recent neuropathological examination provided evidence for TDP-43-positive cytosolic inclusions and dystrophic neurites in the brain of a patient diagnosed with FTLD presenting brief psychotic episodes and catatonia, which is a syndrome related to schizophrenia

Evidence f66fbe2f04

Likewise, the psychostimulant effects experienced by METH-addicted patients rely on increased DA synthesis and massive DA release from nerve terminals within limbic areas as occurring in the schizophrenic brain

Evidence 38fbe67dff

Notably, a marked reduction in MAP2 immunoreactivity, along with a decrease in dendritic arbor, is reported in the primary auditory cortex (BA41) of schizophrenic subjects compared with healthy controls

Evidence 07f0fc0615

Momeni and colleagues (2010) recently reported two relatives with an early age at onset (27 and 29 years) of schizophrenic symptoms showing a marked neuronal tau deposition, as confirmed at pathological examination

Evidence c420e3e8b9

Notably, post-mortem analysis performed in the prefrontal cortex of schizophrenic patients revealed oligodendrocyte ultrastructural abnormalities

Evidence dfac935405

Dysregulation in Akt signaling and altered Akt protein levels were found in the frontal cortex and hippocampus of post-mortem brain samples from individuals affected by schizophrenia

Evidence ea77dd3420

In detail, the analysis of mRNA expression of a key protein for autophagy initiation, namely beclin1, revealed a significant region-specific reduction in hippocampal samples from 12 schizophrenic patients compared with 12 age-matched healthy controls.

Evidence bd4ab60aea

Immuno-histochemical analysis showed a three-fold decrease in the number of beclin1-positive cells in Map6+/- mice

Evidence 5c197c008e

A reduction of ADNP and its homologous protein, ADNP2, is observed in schizophrenic patients [254], and it is recapitulated in Map6-deficient (Map6+/-) mice, another transgenic model of schizophrenia


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