path(MESH:Schizophrenia)
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755
Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273). PubMed:19126755
This study reported that xanomeline treatment produced robust improvements in both the positive and the negative symptoms of patients with SZ PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23). PubMed:17009926
Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression. PubMed:17009926
Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007) PubMed:21482353
Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular PubMed:21482353
Recent studies provide evidence both that nicotinic signaling partially underlies these schizophrenia-related inhibitory defects and that nicotinic drugs have possible therapeutic roles PubMed:21482353
Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002) PubMed:21482353
Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits PubMed:21482353
Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia PubMed:21482353
Third, persons with schizophrenia have the greatest rate and intensity of cigarette smoking of any identifiable subgroup in the population PubMed:21482353
Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999) PubMed:11230871
The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000) PubMed:11230871
Two compounds that are currently in clinical use might have direct effects on the alpha7 nAChR. The anticholinesterase inhibitor galantamine has modulatory effects on alpha7 nAChR and was reportedly beneficial for patients with schizophrenia in a case study184 PubMed:19721446
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176. PubMed:19721446
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
Decreased expression of α7 AChR has also been associated with schizophrenia [51,195–197]. PubMed:22040696
Interestingly, levels of RIC-3 mRNA are elevat- ed in postmortem brains of individuals with bipolar disorder and schizophrenia [181], and a link has been suggested between defi- cient RIC-3 mediated chaperoning of an AChR subunit and individ- uals with bipolar disorder and psychotic symptoms [181]. PubMed:22040696
In fact, lithium is able to delay METH-induced sensitization, while being a powerful treatment in schizophrenia PubMed:30061532
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 PubMed:30061532
Beyond METH, redox-related changes that result from an imbalance between reactive oxygen species (ROS) production and ROS clearance are implicated in schizophrenia PubMed:30061532
Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia PubMed:30061532
Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia PubMed:30061532
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 PubMed:30061532
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) PubMed:30061532
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 PubMed:30061532
In addition, cytoskeletal derangement appears as a prominent feature of the ultrastructural pathology of schizophrenia PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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). PubMed:30061532
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). PubMed:30061532
Another identified susceptibility gene for schizophrenia is the dihydropyrimidinase-like 2 (DPYSL2) gene PubMed:30061532
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). PubMed:30061532
In addition, these findings strongly suggest that DISC1 alterations may increase the risk of schizophrenia by dysregulating DA release PubMed:30061532
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 PubMed:30061532
Increased activity of D1R is considered as a major determinant of neuropsychiatric alterations occurring in both METH models/abusers and in schizophrenia PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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) PubMed:30061532
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) PubMed:30061532
Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755
In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755
Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273). PubMed:19126755
Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233
Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics. PubMed:24511233
Another commonality between AD and SZ is the apparent involvement of dysregulated cholinergic signaling in the brain. PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported PubMed:24511233
Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23). PubMed:17009926
Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression. PubMed:17009926
Recent studies provide evidence both that nicotinic signaling partially underlies these schizophrenia-related inhibitory defects and that nicotinic drugs have possible therapeutic roles PubMed:21482353
Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits PubMed:21482353
Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular PubMed:21482353
In many persons with schizophrenia, cerebral evoked potential recording shows diminished inhibition of the response to repeated stimuli (Adler et al., 1982) (Figure 2A), and animal models of this phenomenon point to a defect in hippocampal inhibition PubMed:21482353
Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002) PubMed:21482353
Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007) PubMed:21482353
Third, persons with schizophrenia have the greatest rate and intensity of cigarette smoking of any identifiable subgroup in the population PubMed:21482353
Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia PubMed:21482353
The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000) PubMed:11230871
Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999) PubMed:11230871
Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999) PubMed:11230871
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173. PubMed:19721446
nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176. PubMed:19721446
in addition, a decrease in alpha7 nAChR density in the hippocampus of patients with schizophrenia has been reported177. Similarly, a low density of alpha7 nAChRs in inbred strains of mice is associated with poor gating178. Recently, the expression of a novel variant of alpha7 nAChR, CHRNA7-2 (cholinergic receptor, nicotinic, alpha7, variant 2), was found to be reduced below control levels in the prefrontal cortex of patients with schizophrenia179. PubMed:19721446
Decreased expression of α7 AChR has also been associated with schizophrenia [51,195–197]. PubMed:22040696
Interestingly, levels of RIC-3 mRNA are elevat- ed in postmortem brains of individuals with bipolar disorder and schizophrenia [181], and a link has been suggested between defi- cient RIC-3 mediated chaperoning of an AChR subunit and individ- uals with bipolar disorder and psychotic symptoms [181]. PubMed:22040696
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) PubMed:30061532
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) PubMed:30061532
Increased activity of D1R is considered as a major determinant of neuropsychiatric alterations occurring in both METH models/abusers and in schizophrenia PubMed:30061532
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). PubMed:30061532
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 PubMed:30061532
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). PubMed:30061532
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). PubMed:30061532
Another identified susceptibility gene for schizophrenia is the dihydropyrimidinase-like 2 (DPYSL2) gene PubMed:30061532
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 PubMed:30061532
In addition, the occurrence of alpha synuclein gene (SNCA) polymorphisms is associated with human METH psychosis [166]. PubMed:30061532
Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia PubMed:30061532
Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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]. PubMed:30061532
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 PubMed:30061532
Beyond METH, redox-related changes that result from an imbalance between reactive oxygen species (ROS) production and ROS clearance are implicated in schizophrenia PubMed:30061532
In addition, cytoskeletal derangement appears as a prominent feature of the ultrastructural pathology of schizophrenia PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
Notably, post-mortem analysis performed in the prefrontal cortex of schizophrenic patients revealed oligodendrocyte ultrastructural abnormalities PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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) PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532
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 PubMed:30061532
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. PubMed:30061532
Immuno-histochemical analysis showed a three-fold decrease in the number of beclin1-positive cells in Map6+/- mice PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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 PubMed:30061532
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.