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Possible cause of HPPD: Hyperactive mTORC1


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Hello everyone!
The following is a bunch of research on how, through the modulating of mTOR, we could arrive at our present situation. my apologies for the lackluster organization. its a lot. 
 
"Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB. Moreover, the inactivation of mPFC glutamate neurotransmission impairs SB and nullifies the prosocial effects of LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic, but not in inhibitory neurons, to produce prosocial effects. This study unveils a mechanism contributing to the role of 5-HT2A agonism in the modulation of SB."
 
Why is this important? Well mTor is how our body regulates EVERYTHING.
 
  • The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine/threonine kinase that is present in two complexes, mTORC1 and mTORC2. mTORC1 is the main energy and nutrient sensor of the cell: it senses the presence of amino acids, glucose, lipids and ATP to allow efficient activation of the network in response to growth factors, Toll-like receptor ligands and cytokines.
  • Activation of the mTOR pathway usually promotes an anabolic response that induces the synthesis of nucleic acids, proteins and lipids. In addition, it stimulates glycolysis as well as mitochondrial respiration. Emerging data suggest that this metabolic reconfiguration is required for specific effector functions in myeloid cells.
  • Translational control of gene expression in myeloid immune cells emerges as one way in which mTORC1 controls cellular processes such as migration, interferon and pro- or anti-inflammatory cytokine expression as well as metabolic reprogramming.
  • The mammalian target of rapamycin (mTOR) integrates the intracellular signals to control cell growth, nutrient metabolism, and protein translation. mTOR regulates many functions in the development of the brain, such as proliferation, differentiation, migration, and dendrite formation. In addition, mTOR is important in synaptic formation and plasticity. Abnormalities in mTOR activity is linked with severe deficits in nervous system development, including tumors, autism, and seizures. Dissecting the wide-ranging roles of mTOR activity during critical periods in development will greatly expand our understanding of neurogenesis.
  • Inhibition of mTORC1 in macrophages promotes autophagy, which is important for intracellular pathogen killing and clearance of ingested complex lipids such as LDL cholesterol.
 
lets start with autophagy

 

Soo... whats autophagy? and how does it relate to mTOR?
 

 

Autophagy and mTOR
As a key regulator of autophagy, the mTOR plays an important role in autophagy, translation, cell growth and survival (Hwang et al., 2017). Mammalian target of rapamycin and autophagy are tightly bound within cells, and defects of mTOR and autophagy process might lead to a variety of human diseases (Hoeffer and Klann, 2010). Studies have shown that mTOR is widely involved in autophagy activation and synaptic plasticity (Ryskalin et al., 2018). The mTOR modulates long-lasting synaptic plasticity, memory and learning via regulating the synthesis of dendritic proteins (Liu et al., 2018a). Macroautophagy can degrade organelles and long-lived proteins in case of mTOR inactivation. Synaptic plasticity is further modulated by mTOR and neurodegeneration occurs when macroautophagy is absent (Hernandez et al., 2012). Therefore, macroautophagy following mTOR inactivation at the presynaptic terminal rapidly changes the neural transmission and presynaptic structure (Hernandez et al., 2012). The mechanisms for the target of rapamycin have been involved in modulating neurodegeneration and synaptic plasticity, but the role of mTOR in regulating presynaptic function via autophagy has not been clarified clearly (Torres and Sulzer, 2012).
In summary, there is a close relationship among mTOR, brain plasticity and autophagy. The mTOR related pathways play important role in regulating the process of autophagy and brain plasticity.
 
Autophagy is a lysosome-reliant degradation mechanism that regulate many biological courses, such as neuroprotection and cellular stress reactions (Shen and Ganetzky, 2009). There are different kinds of autophagy in most mammalian cells, and each type of autophagy performs very specific tasks in the course of intracellular degradation (Tasset and Cuervo, 2016). The autophagy-lysosomal pathway is a main proteolytic pathway, which mainly embraces chaperone-mediated autophagy and macroautophagy in mammalian systems (Xilouri and Stefanis, 2010). Macroautophagy, as a lysosomal pathway in charge of the circulation of long-lived proteins and organelles, is mainly considered as the inducible course in neurons, which is activated in conditions of injury and stress (Boland and Nixon, 2006). Coupled with macro-autophagy, chaperone-mediated autophagy (CMA) is crucial for maintaining intracellular survival and homeostasis via selectively reducing oxidized, misfolded, or degraded cytoplasmic proteins (Cai et al., 2015).
The plasticity of the central nervous system(CNS) can be regarded as changes of functional interaction between different types of cells, astrocytes, neurons, and oligodendrocytes (Aberg et al., 2006). The mature brain, as a highly dynamic organ, constantly alters its structure via eliminating and forming new connections. In general, these changes are known as brain plasticity and are related to functional changes (Viscomi and D’Amelio, 2012). Brain plasticity can be divided into structure plasticity and function plasticity. The structural plasticity of the brain refers to the fact that the connections between synapses and neurons in the brain can be established due to the influence of learning and experience. It includes the plasticity of synapses and neurons. Synaptic plasticity refers to the changes of pre-existing relationship between two neurons including structure and function alteration (De Pitta et al., 2016). Synaptic plasticity is considered as the representative of cellular mechanisms of memory and learning. Mitochondria are related to the modulation of complicated course of synaptic plasticity (Todorova and Blokland, 2017). For a long period, synaptic plasticity has been considered as a neuronal mechanism under the regulation of neural network action (Ronzano, 2017). Recent data indicate that autophagy is a homeostatic mechanism which is compatible with the microenvironment of the synapse, with the purpose of serving local functions linked with synaptic transmission (Todorova and Blokland, 2017). Neuronal plasticity is maintained by the fine modulation of organelle biogenesis and degradation and protein synthesis and degradation to assure high-efficiency turnover (Viscomi and D’Amelio, 2012). Protein degradation plays an important role in the course of synaptic plasticity, but the involved molecular mechanisms are unclear (Haynes et al., 2015). Therefore, Autophagy is a quality control mechanism of organelles and proteins in neurons, which plays a crucial role in their physiology and pathology (Viscomi and D’Amelio, 2012). In a word, there is a close relationship between autophagy and brain plasticity, and the related mechanisms are summarized in this review paper (as Table 1 and Figure 1 demonstrate).
 
mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process.
_______________________________________________

 

So... weve hyperactived our mTORC1.... we cannot initiate the autophagy process... what does this mean???
 
1) Hyperactivation of mTORC1 by TSC1/2 deletion induces aberrant growth, proliferation, and differentiation of neurons and astrocytes, resulting in neuronal dysplasia, abnormal neuronal architecture, reactive astrogliosis, and seizures (27, 40,42).
 
Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells
Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolism. The importance of mTORC1 signaling in neuronal development and functions has been highlighted by its strong relationship with many neurological and neuropsychiatric diseases. Previous studies demonstrated that hyperactivation of mTORC1 in forebrain recapitulates tuberous sclerosis and neurodegeneration. In the mouse cerebellum, Purkinje cell-specific knockout of Tsc1/2 has been implicated in autistic-like behaviors. However, since TSC1/2 activity does not always correlate with clinical manifestations as evident in some cases of tuberous sclerosis, the intriguing possibility is raised that phenotypes observed in Tsc1/2 knockout mice cannot be attributable solely to mTORC1 hyperactivation. Here we generated transgenic mice in which mTORC1 signaling is directly hyperactivated in Purkinje cells. The transgenic mice exhibited impaired synapse elimination of climbing fibers and motor discoordination without affecting social behaviors. Furthermore, mTORC1 hyperactivation induced prominent apoptosis of Purkinje cells, accompanied with dysregulated cellular homeostasis including cell enlargement, increased mitochondrial respiratory activity, and activation of pseudohypoxic response. These findings suggest the different contributions between hyperactivated mTORC1 and Tsc1/2 knockout in social behaviors, and reveal the perturbations of cellular homeostasis by hyperactivated mTORC1 as possible underlying mechanisms of neuronal dysfunctions and death in tuberous sclerosis and neurodegenerative diseases.
 
neurogenesis, dendrite formation, and synaptic integration:
Effects of mTOR activation during neurogenesis. Neural stem cells (blue) undergo proliferation and either give rise to more stem cells (self-renewal) or daughter cells (green, differentiation). Activation of mTORC2 promotes neural stem cells (NSC) cell cycle entry through Akt. Hyperactivation of mTORC1 results in diminished self-renewal, favoring differentiation and lineage expansion. Daughter cells then migrate (red) from proliferation zones to their terminal positions. Activation of mTORC1 results in aberrant migration of daughter cells. Upon reaching their terminal positions, newly born neurons (gray) extend neurites and properly form dendritic arbors. Cells with high levels of mTORC1 activity can severely alter dendrite formation and synaptic integration. Upward pointing arrows indicate increased activity of designated genes or proteins. Downward pointing arrows indicate decreased activity or knockdown of designated genes or proteins. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983636/
 
 
Mitochondria:
 
 
Induction of cellular stresses by mTORC1 hyperactivation
We explored the molecular mechanisms underlying Purkinje cell death by mTORC1 hyperactivation in PC-mTOR Tg mice. Activation of mTORC1 enhances the mitochondrial biogenesis by forming a complex with PGC1α and YY124. We observed mitochondrial morphology in Purkinje cells by using the electron microscopy (Fig. 6a–f). As expected, the remarkably enlarged mitochondria were often found in PC-mTOR Tg mice in both cell bodies (Fig. 6a and b) and dendrites (Fig. 6e and f) compared to control mice. Despite their abnormal morphology, the internal lamellar structure of cristae was almost preserved even in enlarged mitochondria in PC-mTOR Tg mice (Fig. 6c and d). To test the mitochondrial respiratory activity, the cytochrome c oxidase activity was visualized in the cerebellar slices. Mitochondrial activity was detected in both molecular and Purkinje cell layers of control mice (Fig. 6g and h). Although similar staining patterns were also observed in PC-mTOR Tg mice, the cell bodies of Purkinje cells were stained more densely than control mice. Thus, despite their abnormal morphology, the mitochondrial respiratory function was not impaired but rather enhanced in Purkinje cells of PC-mTOR Tg mice.
 
Glutamate
To assess the pre- and postsynaptic function of each mTOR complex in glutamatergic synaptic transmission, we inactivated mTORC1 signaling by conditionally deleting Raptor, or mTORC2 signaling by conditionally deleting Rictor, postmitotically in primary neuron cultures from mouse hippocampus. We then performed morphological and whole-cell patch-clamp analysis of synaptic and membrane properties of glutamatergic neurons. Our results showed that both mTOR complexes were necessary to support normal neuron growth and evoked excitatory synaptic transmission. Despite these similarities, the effects of mTORC1 on evoked EPSCs (eEPSCs) were postsynaptic, via reductions in synapse number, whereas mTORC2 regulated the presynaptic Ca2+ dependence of evoked SV release. Furthermore, although the mechanism through which mTORC1 inactivation decreased eEPSCs was postsynaptic, it also increased spontaneous SV release and SV pool replenishment, which are thought to be presynaptic processes. Overall, each mTOR complex affected distinct modes of SV release: mTORC1 inactivation enhanced modes with low rates of SV fusion, such as spontaneous release, and mTORC2 inactivation impaired modes with high rates of SV fusion, such as action potential-evoked release. Thus, via differential activation of these two complexes, the mTOR pathway is ideally poised to respond to external cues and make fine adjustments to glutamatergic synaptic transmission to maintain normal neural network function.
Previous studies showed that mTOR inhibition by rapamycin treatment reduces the number of AMPA receptors at the synapse (Wang et al., 2006), the number of synapses (Weston et al., 2012), and the number of SVs per synapse (Hernandez et al., 2012). Accordingly, mTOR hyperactivation increases mEPSC amplitude (Xiong et al., 2012), AMPA receptor number, and spine density (Tang et al., 2014Williams et al., 2015), and these effects are blocked by rapamycin. Thus, integrating our findings on specific mTORC1 inactivation with these previous findings, several lines of evidence now indicate that mTORC1 acts via a postsynaptic mechanism to bidirectionally regulate evoked glutamatergic synaptic strength.
 

 

GABA: We have FUCKED gaba (but you knew that didn't you)
The following is evidence of the reduced gaba hypothesis that is thrown around a lot. basically, disrupting the autophagy from mTOR (such as that which would occure through hyperactive MTORC1) causes a reduction in the surface expression of GABA A receptors ( thats the ones benzos increase activity on). The following is two studies, one is a good tldr and the other is much mor indepth.
 

 

Autophagy links MTOR and GABA signaling in the brain
The disruption of MTOR-regulated macroautophagy/autophagy was previously shown to cause autistic-like abnormalities; however, the underlying molecular defects remained largely unresolved. In a recent study, we demonstrated that autophagy deficiency induced by conditional Atg7 deletion in either forebrain GABAergic inhibitory or excitatory neurons leads to a similar set of autistic-like behavioral abnormalities even when induced following the peak period of synaptic pruning during postnatal neurodevelopment. Our proteomic analysis and molecular dissection further revealed a mechanism in which the GABAA receptor trafficking function of GABARAP (gamma-aminobutyric acid receptor associated protein) family proteins was compromised as they became sequestered by SQSTM1/p62-positive aggregates formed due to autophagy deficiency. Our discovery of autophagy as a link between MTOR and GABA signaling may have implications not limited to neurodevelopmental and neuropsychiatric disorders, but could potentially be involved in other human pathologies such as cancer and diabetes in which both pathways are implicated.
 

 

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior

 

Excessive p62 accumulation in autophagy-deficient and mTOR-hyperactivated neurons results in reduced GABAA receptor surface expression due to mislocalized GABARAPs
We next asked whether the observed disruption of GABAA receptor trafficking is specific to autophagy-deficient conditions or is due to a general increase in p62 levels. First, by immunofluorescence, we found that p62 overexpression in WT neurons led to the formation of p62+ aggregates that also sequestered GABARAPs (Fig. 5A and fig. S7, A to C). Second, we observed a significant reduction in surface GABAA receptors in WT neurons with p62 overexpression (Fig. 5B). Third, if the reduced surface expression of GABAA receptors was caused by sequestration of GABARAPs by p62, a reduction of p62 in Atg7 cKO neurons would be expected to restore such deficits. To test this hypothesis, we performed surface receptor biotinylation experiments on Atg7 cKO and control neurons with or without Sqstm1 (p62) knockdown. Consistent with our prediction, Sqstm1 knockdown in Atg7 cKO neurons reversed the reduction of surface GABAA receptors to control levels (Fig. 5C). Together, this series of experiments suggests that the pathologic accumulation of p62 in Atg7 cKO neurons sequesters GABARAPs and disrupts the normal functions of GABARAPs, resulting in a reduction of surface GABAA receptor levels.
 
 
Astrocytes: here we go
Astrocyte activation has been implicated in the pathogenesis of several neurological conditions, such as neurodegenerative diseases, infections, trauma, and ischemia. Reactive astrocytes are capable of producing a variety of pro-inflammatory mediators, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), neurotrophic factors [1], as well as potentially neurotoxic compounds, like nitric oxide (NO). NO, one of the smallest known bioactive products of mammalian cells, is biosynthesized by three distinct isoforms of NO synthase (NOS): the constitutively expressed neuronal (n)NOS and endothelial (e)NOS, and the inducible (i)NOS [2]. The expression of iNOS can be induced in different cell types and tissues by exposure to immunological and inflammatory stimuli [3]. In vitro, primary astrocyte cultures express iNOS in response to cytokines such as IL-1β [4], interferon γ (IFNγ), TNFα and/or the bacterial endotoxin, lipopolysaccharide (LPS) [5, 6]. Once induced, iNOS leads to continuous NO production, which is terminated by enzyme degradation, depletion of substrates, or cell death [7]. iNOS activity generates large amounts of NO (within the μM range) that can have antimicrobial, anti-atherogenic, or apoptotic actions [8]. However, aberrant iNOS induction exerts detrimental effects and seems to be involved in the pathophysiology of several human diseases [9, 10].
 
soo... this is where it gets bad.

 

This study has revealed that the inactivation of mTORC1 in postmitotic neurons causes moderate reactive astrogliosis. The loss of neural mTORC1 activity may induce astrogliosis by reducing the neuronal secretion of FGF-2, thereby inhibiting FGF receptor signaling in astrocytes, which is required to maintain their nonreactive state (36) (Fig. 7). Although our present data could not identify the exact role of FGF-2 in this process, and the underlying mechanism needs to be further investigated, our findings have uncovered a novel mechanism for the regulation of astrocytes by dysfunctional neurons and have established a potential important link between mTORC1 signaling and CNS pathologies.
The function of mTORC1 in neurons and astrocytes has been extensively studied in conditional knock-out mice (26, 37,39). Hyperactivation of mTORC1 by TSC1/2 deletion induces aberrant growth, proliferation, and differentiation of neurons and astrocytes, resulting in neuronal dysplasia, abnormal neuronal architecture, reactive astrogliosis, and seizures (27, 40,42). Inactivation of mTORC1 in neuronal progenitors impairs the growth and proliferation of neurons and astrocytes, resulting in a smaller brain and in death shortly after birth (25, 43).
 
Lets talk about INFLAMMATION: OMG THE SYMPTOMS
 
So we see that mTORC1 Hyperactivation results in an increase in cytokines. One of those is il-1b.... and its nefarious in the brain.
 
IL-1b
 
Steps:
1. Increase in mTORC1
2. increase in IL-1b proinflammatory cytokine
3. decrease in cb1 recebtor binding
4. decreases CB1R's (gabaA) synapse binding in the striatum
5. causes behavioral manifestations closely resembling anxious-depressive symptoms in humans, including anhedonia, reduced exploratory behaviors, social withdrawal, fatigue, and sleep disturbances
6. This entire process requires "intact function of the transient receptor potential vanilloid 1 (TRPV1)" to work.
 
 
IL-1beta, but not IL-10 or tumour necrosis factor (TNF)-alpha, down-regulated the surface expression and Ser831 phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1. Agents that block IL-1beta receptor activity abolished these effects. In contrast, no change in the surface expression of the N-methyl-d-aspartate (NMDA) receptor subunit NR1 was observed.
The inhibition of NMDA receptor activity or depletion of extracellular calcium blocked IL-1beta effects on GluR1 phosphorylation and surface expression. NMDA-mediated calcium influx was also regulated by IL-1beta.
These findings suggest that IL-1beta selectively regulates AMPA receptor phosphorylation and surface expression through extracellular calcium and an unknown mechanism involving NMDA receptor activity.
(PS Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory)
 
Blood brain barrier:
On the other hand, interleukin (IL)-1β significantly induces the production of MMP 1, 3, 10, and 13 via a mechanism that is independent of Ca2+
In summary, the results presented here are the first to reveal the function of MMP3 in the BBB and suggest that it has an essential role in the brain microvasculature that differs from its function in other vessels. We have shown that MMP3 increases BBB permeability by upregulating the ERK signaling pathway, which subsequently reduces TJ and AJ protein abundance in BMVECs. Oxidative stress often leads to impairment of BBB. Since the BBB is the primary regulator of exchange between the peripheral blood and the brain, our observations likely have important implications for treating neuroinflammatory conditions and other CNS disorders involving the endothelial MMP3 pathway.
 
 
TNF-a: this is a bit scary
 
TNF released by microglia has an important role in regulating synaptic plasticity [110]. Specifically, it controls a process called synaptic scaling, i.e., the adjustment of synaptic strength in response to prolonged changes in the electrical activity of neurons [110,111]. Indeed, a reduction of glutamate transmission increases microglial TNF release, which promotes the expression of AMPA glutamate receptors in neurons. Conversely, increased extracellular glutamate concentration inhibits TNF release from microglia, additional glutamate receptor expression, and declines neuronal activity [111–113]. The increase of AMPA receptor GluR1 subunit expression does not occur at mRNA level, but this is controlled by TNF at post-transcriptional level [114]. Subsequent studies revealed that TNF facilitates the trafficking and membrane insertion of AMPA receptors at the neuron surface, which are crucial for the homeostatic synaptic plasticity. Specifically, hippocampal neurons exposed to TNF increase surface expression of GluR1 subunit through modulation of NF-κB and acid sphingomyelinase pathways [115]. TNF not only controls homeostatic synaptic activity, but also induces neurotoxicity via autocrine/paracrine loops involving other endogenous mediators. First, TNF activates TNFR1 on microglia, amplifying its production and release [95]. Second, microglia-derived TNF activates TNFR1 expressed on astrocytes, allowing glutamate release from the glial cells. This, in turn, activates its specific receptors, including the metabotropic mGluR2 receptor on microglia, potentiating microglial TNF production and affecting synaptic transmission [110]. ATP, released by microglia concurrently with TNF, contributes to TNF-mediated neuronal damage by inducing a prolonged activation of microglial P2X7 receptor and release of both IL-1β and TNF inflammatory cytokines. In addition, both microglial TNF and ATP trigger adjacent astrocytes to release additional ATP, that amplifies microglia response and promotes astroglial release of glutamate, aggravating neuronal dysfunction [110]. Moreover, TNF mediates neuronal death by increasing extracellular levels of the excitotoxic transmitter glutamate and excessive AMPA receptor activation via downregulation of the astrocytic glutamate transporter EAAT2/GLT1 [116]. The effects of TNF on N-methyl-D-aspartate receptors (NMDARs) trafficking are less characterized. However, it has been demonstrated that, in hippocampal neurons, TNF increases the expression of the NR1 subunit of NMDAR and its specific clustering into lipid rafts [117]. Accordingly, treatment of human neuronal cultures with competitive (2-APV) and noncompetitive (MK-801) NMDA receptor antagonists reduced the glutamate neurotoxicity induced by TNF [118].
 
" In MS, glutamate-related excitotoxicity, caused by excessive activation of these receptors (leading to a Ca2+ overload), is responsible for neuronal and oligodendrocyte death [2, 16, 17]. In addition, microglia, the resident macrophages of the CNS, become activated by increased glutamate concentration. Activated microglia proliferate, secrete cytokines, chemokines, nitric oxide and ROS, and may become phagocytic; outcomes all of which cause further injury to the ailing CNS [9]. Oligodendrocytes have been found to be particularly susceptible to glutamate excitotoxicity, via the AMPA/kainate receptors. AMPA/kainate antagonists have been shown to increase oligodendrocyte survival as well as reducing axonal damage [16, 17]. "
--this is important to note because if we have abysmal gaba and high glutamate from the mTORC1 and from astrocyte issues then excitotoxic events are easily understandable. Here you can see how these events could lead to an out-of-control inflammatory response.

 

What do we do???? BEATS ME REALLY but heres some options
reduce mtor?
 
 
Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration
mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration.
 
 
Autophagy Dysfunction and mTOR Hyperactivation Is Involved in Surgery: Induced Behavioral Deficits in Aged C57BL/6J Mice
 
Autophagy is crucial for cell survival, development, division, and homeostasis. The mammalian target of rapamycin (mTOR), which is the foremost negative controller of autophagy, plays a key role in many endogenous processes. The present study investigated whether rapamycin can ameliorate surgery—induced cognitive deficits by inhibiting mTOR and activating autophagy in the hippocampus. Both adult and aged C57BL/6J mice received an intraperitoneal injection of rapamycin (10 mg/kg/day) for 5 days per week for one and a half months. Mice were then subjected to partial hepatectomy under general anesthesia. Behavioral performance was assessed on postoperative days 3, 7, and 14. Hippocampal autophagy-related (Atg)-5, phosphorylated mTOR, and phosphorylated p70S6K were examined at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, and tau hyperphosphorylation (T396) in the hippocampus were also examined. Surgical trauma and anesthesia exacerbated spatial learning and memory impairment in aged mice on postoperative days 3 and 7. Following partial hepatectomy, the levels of phosphorylated mTOR, phosphorylated 70S6K, and phosphorylated tau were all increased in the hippocampus. A corresponding decline in BDNF and synaptophysin were observed. Rapamycin treatment restored autophagy function, attenuated phosphorylation of tau protein, and increased BDNF and synaptophysin expression in the hippocampus of surgical mice. Furthermore, surgery and anesthesia induced spatial learning and memory impairments were also reversed by rapamycin treatment. Autophagy impairments and mTOR hyperactivation were detected along with surgery—induced behavioral deficits. Inhibiting the mTOR signaling pathway with rapamycin successfully ameliorated surgery-related cognitive impairments by sustaining autophagic degradation, inhibiting tau hyperphosphorylation, and increasing synaptophysin and BDNF expression. https://link.springer.com/article/10.1007/s11064-019-02918-x

 

Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes
In summary, this study has demonstrated that the inactivation of mTORC1 in postmitotic neurons induces reactive astrogliosis, possibly by inhibiting FGF-2 secretion. mTORC1 activity in postmitotic neurons is required for maintaining astrocytes in a nonreactive state. Astrogliosis is likely to be regulated by various signaling pathways and various cell types in different nuclei on the CNS. In our studies, neuronal mTORC1 activity regulates astrocyte activation, possibly via multiple potential signals directly or indirectly. Further investigation is required to define the pathological consequences of astrogliosis induced by the loss of neuronal mTORC1 and its association with CNS disease. Manipulating mTORC1 in neurons or FGF-2 signaling in astrocytes may represent a novel therapeutic mechanism for treating CNS disorders and improving functional recovery in neuropathological conditions.
 
 
Medications: IM NOT A DOCTOR and honestly some of these are pretty extreme. Don't take these without research and consulting a medical professional.
 
The point of these medications:
 
  1. reduce damage caused by reaction. this includes microglial and astrocyte dysfunction and resulting inflammatory markers
  2. treat reaction at source
  3. Repair damage from the reaction
 
Pramipexole:
curative action: DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis
The results revealed that pramipexole induces autophagy through MTOR inhibition and a DRD3-dependent but DRD2-independent mechanism. DRD3 activated AMPK followed by inhibitory phosphorylation of RPTOR, MTORC1 and RPS6KB1 inhibition and ULK1 activation. Interestingly, despite RPS6KB1 inhibition, the activity of RPS6 was maintained through activation of the MAPK1/3-RPS6KA pathway, and the activity of MTORC1 kinase target EIF4EBP1 along with protein synthesis and cell viability, were also preserved. This pattern of autophagy through MTORC1 inhibition without suppression of protein synthesis, contrasts with that of direct allosteric and catalytic MTOR inhibitors and opens up new opportunities for G protein-coupled receptor ligands as autophagy inducers in the treatment of neurodegenerative and psychiatric diseases.
 
Palliative: this will help with the astrocyte insanity/out of control inflammatory cycle
Experimental autoimmune encephalomyelitis (EAE) is the most used animal model of multiple sclerosis (MS) for the development of new therapies. Dopamine receptors can modulate EAE and MS development, thus highlighting the potential use of dopaminergic agonists in the treatment of MS, which has been poorly explored. Herein, we hypothesized that pramipexole (PPX), a dopamine D2/D3 receptor-preferring agonist commonly used to treat Parkinson's disease (PD), would be a suitable therapeutic drug for EAE. Thus, we report the effects and the underlying mechanisms of action of PPX in the prevention of EAE. PPX (0.1 and 1 mg/kg) was administered intraperitoneally (i.p.) from day 0 to 40 post-immunization (p.i.). Our results showed that PPX 1 mg/kg prevented EAE development, abolishing EAE signs by blocking neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Moreover, PPX inhibited the production of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α in peripheral lymphoid tissue. PPX was also able to restore basal levels of a number of EAE-induced effects in spinal cord and striatum, such as reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein (α-syn). Thus, our findings highlight the usefulness of PPX in preventing EAE-induced motor symptoms, possibly by modulating immune cell responses, such as those found in MS and other T helper cell-mediated inflammatory diseases.
 
Levetiracetam:
The results indicated that TPM and LEV alleviated behavioral deficits and reduced amyloid plaques in APPswe/PS1dE9 transgenic mice. TPM and LEV increased Aβ clearance and up‐regulated Aβ transport and autophagic degradation. TPM and LEV inhibited Aβ generation and suppressed γ‐secretase activity. TPM and LEV inhibited GSK‐3β activation and increased the activation of AMPK/Akt activation. Further, TPM and LEV inhibited histone deacetylase activity in vivo.
  • activation of the ampk pathway reduces mtorc1
 
Baclofen: possible brain healing
GABA receptors play an important role in ischemic brain injury. Studies have indicated that autophagy is closely related to neurodegenerative diseases. However, during chronic cerebral hypoperfusion, the changes of autophagy in the hippocampal CA1 area, the correlation between GABA receptors and autophagy and their influences on hippocampal neuronal apoptosis have not been well established. Here, we found that chronic cerebral hypoperfusion resulted in rat hippocampal atrophy, neuronal apoptosis, enhancement and redistribution of autophagy, down-regulation of Bcl-2/Bax ratio, elevation of cleaved caspase-3 levels, reduction of surface expression of GABAA receptor α1 subunit and an increase in surface and mitochondrial expression of connexin 43 (CX43) and CX36. Chronic administration of GABAB receptors agonist baclofen significantly alleviated neuronal damage. Meanwhile, baclofen could up-regulate the ratio of Bcl-2/Bax and increase the activation of Akt, GSK-3β and ERK which suppressed cytodestructive autophagy. The study also provided evidence that baclofen could attenuate the decrease in surface expression of GABAA receptor α1 subunit and down-regulate surface and mitochondrial expression of CX43 and CX36, which might enhance protective autophagy. The current findings suggested that, under chronic cerebral hypoperfusion, the effects of GABAB receptors activation on autophagy regulation could reverse neuronal damage.

 

WARNING: baclofen interacts with ampa receptors causing an initial increase and then what seems like long term decrease. since there could be a loss of ampa function (whether through cell death or otherwise) this could worsen certain symptoms. Mainly low empathy/issues with anhedonia. Ampa receptors play a very complex role in synaptic plasticity, mood, and behavior.
 
I took baclofen in very high doses (100mg per day) a few years ago. It restored my cognition, made me sociopathic (not permanent), hypomanic (god i wish permanent but no), and gave me anhedonia that took 2 years to cease. But hey it actually did work to heal my brain which is neato ** I think i just overdid it. PAWS set in. Homotaurine may help with this should anyone wish to try baclofen for restoring their cognition.
 
 
Rapamycin: the ultimate mtor inhibitor, see basically all the studies.
 
The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes
In our previous studies, we observed that although rapamycin reduced iNOS expression mRNA and activity in microglial cells, and was without effect on astrocyte iNOS activity [21], it caused a rapid significant increase in iNOS mRNA levels in astrocytes induced by two different proinflammatory stimuli. Later time points were not examined; neither was the basis for this contrasting result examined. In the present paper we tested the hypothesis that while at early times rapamycin increases iNOS mRNA, at later times it modifies iNOS mRNA stability. Our results using primary rat astrocytes are consistent with this hypothesis, and suggest that inhibition of mTOR kinase activity in glial cells results in anti-inflammatory actions. Together with the marked anti-inflammatory effects observed in microglial cells [21], these data further provide pre-clinical evidence for a possible clinical use of mTOR inhibitors in the treatment of inflammatory-based CNS pathologies.
 
but.... is it that simple??
Probably not. Inhibiting mtorc1 across the board surely has issues involved with it. These are very complex mechanisms at work... ive come across some stuff saying there are serious pros and cons for using drugs like rapamycin.
 
 
Some good reads:
tldr: Our brains are going fucking nuts. We have out of control inflammation, autophagy problems, gaba is gonnneeeee, glutamate is out of control... the list is almost endless really. There is so much more not mentioned in this post. this is like a giant tree-- you can follow the branches out very far. But it makes sense-- especially with the weird onset times of hppd. Some of this needs time to get bad enough that you notice it.
 
And if the mtor stays dysregulated you wont heal. For whatever reason, in some people it stays stuck. If we can reverse this issue it should provide at least a fair fight for healing. The sooner its dealt with the better as the more time spent in the "active" state of hppd the more damage is being done.
 
So why cant you see this on an MRI? thats a whole nother post. Youd be surprised what you cant see on an mri though lol.
 
One thing that is important to note--- if there is excitotoxicity of glutamate receptors in this process, reducing the thing that is boosting them, even if it is causing the pathology, may make a person feel WORSE initially. Or, likely, there are other things going on here too--- like how hallucinogens open up susceptibility to viral reactivation in the brain.... for another day.
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 In these five patients with positive respond, four of them were given therapy based on LEV, which may indicate LEV as a preferential choice for patients with DEPDC5 variants. Considering the fact that the loss-of-function variants in DEPDC5 will lead to over-activation of the mTOR pathway, the mTOR inhibitor, such as sirolimus or everolimus, may be a complementary treatment for DEDPC5related epilepsy.”

 

https://aepi.biomedcentral.com/articles/10.1186/s42494-020-0011-9

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