Genetic linkage analyses show co-segregation of Akt1 haplotypes with schizophrenia suggesting that the AKT1
gene may be a schizophrenia susceptibility gene (34
). Similarly, genetic studies demonstrated association of AKT1
gene polymorphisms with schizophrenia in a Chinese population (35
). These associations also have been replicated in other studies including the Irish Study of High Density Schizophrenia Families (36
). There is also evidence suggesting significant alterations in Akt1 levels in people with schizophrenia. Lymphocytes from individuals with schizophrenia expressed 68% less Akt1 compared to control subjects (34
). Importantly, Akt1 was reduced in the hippocampus and frontal cortex in post-mortem brain samples from those with schizophrenia relative to controls; in contrast, Akt2 and Akt3 levels were unaffected (34
). However, differences in Akt1 levels derived from post-mortem brain samples must be approached with some caution, given potential variations in levels of intact protein remaining in tissue (dependent in part on the post-mortem interval). Additionally, a potential confounding factor in using post-mortem brain tissue to ascertain Akt1 levels is whether the lower levels seen in the brains of subjects with schizophrenia is due to the illness or a consequence of often chronic treatment with antipsychotic drugs. Emamian et al
. (2004) attempted to control for effects of chronic drug treatment by using a mouse model of chronic antipsychotic treatment using haloperidol (34
). Future studies comparing Akt 1 levels using brain tissue obtained from drug-naïve subjects or subjects with other disorders also treated chronically with antipsychotic medications (i.e.
bipolar disorder) may help to further clarify the association of brain Akt1 levels with schizophrenia.
Akt may also play a role in cognition through its modulation of synaptic plasticity. Studies have demonstrated Akt’s involvement in long-term potentiation and fear conditioning (8
). Akt1 deficiency in mice also results in abnormalities in working memory and changes in prefrontal cortex neuron architecture (7
). Similarly, GSK-3β has been implicated in cognition through its mediation of long-term potentiation and long-term depression (17
). Consistent with these studies the potential association of genetic variation in the AKT1
gene with neurocognition in schizophrenia was examined using a large pool of subjects with schizophrenia (n=641) drawn from the multi-center Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Using the five schizophrenia-associated single nucleotide polymorphisms (SNPs) in the AKT1
gene originally proposed by Emamian et al
. (2004), no significant association with multiple neurocognitive domains was found (37
). More recently, Tan et al
. (2008) examined the relationship of these five AKT1
SNPs to cognition in healthy subjects and found that variants of the gene are associated with differences in specific domains of cognitive function including IQ, executive function and processing speed (38
). Furthermore, one of the SNPs was associated with reduced expression of Akt1 in peripheral lymphocytes and brain grey-matter. This SNP was also associated with brain volume reductions in the caudate bilaterally and right prefrontal cortex (38
). This is consistent with increasing evidence for Akt-mediated regulation of neuronal cell size and Akt/PI3K-mediated cell volume (6
). In focusing on only five SNPs, however, both of the above studies may have missed other SNPs that do indeed play a role in modulation of neurocognition in schizophrenia
Disruption of Akt’s regulation of GSK-3 activity in the brain may also play a role in dysregulation of brain function in disorders such as schizophrenia, and its restoration by antipsychotic medications may contribute to the clinical efficacy of these drugs. Consistent with the finding that Akt1 levels were reduced in the frontal cortex of subjects with schizophrenia, levels of phosphorylated GSK-3β were also reduced in the frontal cortex of people with schizophrenia (34
). However, the relationship between GSK-3 activity and total amounts of GSK-3 in specific brain regions remains unclear. Despite studies demonstrating reductions in overall levels of GSK-3β in the frontal cortex of subjects with schizophrenia, no correlation was found between levels of GSK-3β activity and its levels in the frontal cortices of these subjects (40
). Like Akt1, post-mortem brain tissue was used to determine GSK-3 levels and activity, leaving open the potential confound of variations in GSK-3 activity due to differences in the post-mortem interval or tissue handling. Alternatively, since only total GSK-3 activity was measured, another GSK-3 isoform, GSK-3α, might have compensated for reduced GSK-3β levels in the frontal cortex. Though the physiological consequences of changing GSK-3β levels and/or activity remain to be determined, it has been proposed that the reduction in GSK-3β levels may affect other signaling pathways such as the Wnt pathway (see below).
If these reductions occur early in life, it may lend further credence to the neurodevelopmental model of schizophrenia (41
). Consistent with this, recent work has linked GSK-3 to Disrupted in Schizophrenia 1 (DISC1), a protein involved in brain development and whose gene was found to be disrupted by a balanced chromosomal translocation in a Scottish family with high incidence of schizophrenia (42
). DISC1 directly interacts with GSK-3, resulting in inhibition of GSK-3β activity and subsequent stabilization of β-catenin. Functionally, DISC1’s inhibition of GSK-3β was also shown to regulate proliferation of neuronal precursor cells in both mouse embryonic and adult brains, further arguing for a role for GSK-3 and Wnt pathway signaling in neurodevelopment (42
). However, to date this relationship between DISC1 and GSK-3β has only been demonstrated in mice and similar studies will be needed in humans to make more direct links between DISC1, GSK-3β and schizophrenia.
As for Akt and GSK-3, Wnt signaling abnormalities have also been demonstrated in schizophrenia. Levels of β-catenin are decreased in the brains of people with schizophrenia, presumably due to aberrant regulation of β-catenin degradation mediated by activated GSK-3β (5
). This is consistent with Emamian et al
.’s findings (2004) demonstrating enhanced GSK-3β activity secondary to diminished phosphorylation by Akt, because levels of Akt are reduced in regions of the brain in those with schizophrenia (34
). Moreover, increased expression of Wnt-1, an important molecule in the Wnt pathway, has been found in the hippocampus of subjects with schizophrenia relative to control subjects (43
). Genetic association analyses have also demonstrated a strong association between the locus for a gene encoding a Wnt receptor, FZD3, and schizophrenia in a Chinese population (44
). Additionally, recent work found associations between genes in the Wnt signaling pathway and psychotic subtypes of bipolar disorder (46
). This further suggests a potential role for the Wnt pathway in psychosis and as a potential target for antipsychotic drugs.