Drug Targets and Neurobiology of Schizophrenia

Schizophrenia is a severe mental disorder that affects around 1% of the global population. Though there is evidence that suggests that schizophrenia is due to a consequence of complex interactions between environmental influences and genetic factors, its etiology is still not known.

The psychiatric condition’s symptoms can be split into three broad categories: cognitive, such as disordered speech, attention deficits, and memory problems; positive symptoms, such as delusions and hallucinations; and negative symptoms, such as diminished affective response, social withdrawal, and lack of interest.

Genetic Factors

Traditionally, schizophrenia has been considered to be a genetic disorder, with heritability rates of between 73-90%. This hypothesis was reinforced by genome-wide association studies (GWAS) performed in the mid-2000s showing schizophrenia-associated genetic alterations, which included large recurrent microdeletions, copy number variations, in addition to rare chromosomal duplications and microdeletions, particularly in neurodevelopmental pathways.

These genomic observations have also suggested that the risk of schizophrenia is associated with polygenic pathways involving thousands of common alleles, each with a minute effect. More recently, GWAS have reduced the list of genetic loci, which are potentially associated with schizophrenia.

These genes include those encoding serotonin 5-HT2A (HTR2A) and dopamine D2 (DRD2) receptors, in addition to genes encoding proteins involved in glutamatergic neurotransmission, voltage-gated ion channels, and the signaling complex which is formed by activity-regulated cytoskeleton-associated scaffold protein (ARC) at the postsynaptic density.

Schizophrenia-associated loci are not dispersed randomly throughout genes of separate functions and classes. They correspond with genes expressed in particular tissues and cell types. Schizophrenia associations are also heightened among genes expressed in tissues with crucial immune functions.

Neural Circuits Associated with Schizophrenia

Figure 1

The thalamus plays a key role in the bidirectional flow of cellular signaling between subcortical and cortical brain areas.

The principal source of glutamatergic (Glu) excitatory axon terminals in the cortex is pyramidal neurons. Axons from dopaminergic (DA) neurons in the mesencephalon and from neurons in the thalamus innervate targets in the frontal cortex.

It has been proposed that an excessive response of pyramidal neurons in the frontal cortex is a mechanism of psychosis. The release of dopamine from the ventral tegmental nucleus activates dopamine D1 and D2 receptors, which increase the pyramidal neuronal response to glutamate.

Cortical 5-HT2A receptors are activated by serotonin (5-HT) release from the dorsal raphe nucleus. This prompts the release of glutamate. Antipsychotic drugs modulate the effects of both serotonin and dopamine, in addition to blocking dopamine signaling in the substantia nigra, which has been implicated in movement disorders.

Antipsychotics modulate the release of acetylcholine from the basal forebrain nucleus, while they also heighten interneuron activity by blocking noradrenaline (NA) receptors in the locus coeruleus. Interneurons in the frontal cortex regulate glutamate release and hence the excitation of cortical pyramidal neurons.

Environmental Events

Although a fundamental role in the etiology of schizophrenia is played by genetics, genetic aberrations are not the sole influence responsible for this psychiatric phenotype. The concordance rates of schizophrenia for monozygotic twins, whose DNA sequences are around 100% identical, have been discovered to be approximately 40 to 50%, which shows that environmental events in the development of schizophrenia are significant.

Epidemiological studies suggest that maternal infection with a large scope of microbial agents, which include the influenza virus, heightens the risk of developing schizophrenia in later life. Likewise, severe adverse life events during pregnancy such as famine, war, and death of a close relative have been related to schizophrenia risk in the adult offspring.

Animal models of maternal stress and maternal influenza viral infection, endorse a consistent conclusion that schizophrenia-related behavioral and physiological alterations in the offspring are related to inflammatory mediators which are found in amniotic fluid and maternal blood. It remains unknown if these proteins cross the placenta and act directly upon the fetal brain.

However, these animal models have identified several cytokines as critical mediators of maternal immune activation, which has been thought to cause dysbiosis of the offspring gut microbiota. These alterations, which are connected to prenatal insults influence schizophrenia-related phenotypes in the adult offspring.

Figure 2

Current and Emerging Targets for Schizophrenia

Cell Signaling

Figure 3

Several Gq protein-coupled receptors, including the metabotropic glutamate 5 (mGlu5), serotonin 5-HT2A, and acetylcholine muscarinic M1, have been suggested as direct targets of either antipsychotic drugs or drugs which produce antipsychotic-related behaviors in rodent models.

Activation of Gq protein-coupled receptors evokes the phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4, 5 bisphosphate (PIP2), which ultimately prompts a transient increase in the concentration of intracellular calcium [Ca2+]i via the release of Ca2+ from the endoplasmic reticulum.

A key mechanism for changing the shape, and hence the function of a protein, is removing or adding phosphates. The MAPKs are a family of serine/threonine kinases which include extracellular signal-regulated kinases like ERK1/2. The downstream effectors of MAPKs modulate several cellular functions, these include transcriptional regulation, cell cycle, and apoptosis.

Both β-arrestin- and G protein-mediated signaling cascades might result in ERK activation. Yet, the subcellular distribution of activated ERK1/2 downstream of these two pathways is not the same. The phosphorylated ERK1/2 induced by β-arrestin stays in the cytoplasm, whereas phosphorylated ERK1/2 mediated via heterotrimeric G protein signaling translocates into the nucleus.

Glutamatergic Hypofunction

One of the fundamental hypotheses underlying the pathophysiology of schizophrenia is glutamatergic hypofunction.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, for example, phencyclidine (PCP), are employed as pharmacological models of schizophrenia in rats and mice due to their capacity to instigate psychotic symptoms in humans, in addition to deficits in sensorimotor gating resembling those seen in the disease.

The utilization of NMDA-enhancing agents, like D-Serine, sarcosine, and glycine, has been suggested as a potential pharmacological method to augment the therapeutic potential of antipsychotic medications currently available. Genes that make up part of the postsynaptic NMDA receptor-PSD95 signaling complex have been connected with the etiology of schizophrenia.

Adenylyl Cyclase

Figure 4

Gi/o protein-coupled receptors, like acetylcholine muscarinic M4, metabotropic glutamate 2 (mGlu2), dopamine D2, and α2A adrenergic, have been shown to act as direct targets of antipsychotic drugs.

Activation of Gi/o protein-coupled receptors results in both positive regulations of K+ channels by the Gβγ subunit and inhibition of adenylate cyclase activity by the Gαi subunit. This influences the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), and so, the activity of protein kinase A (PKA).

Regulation of Gene Transcription

Figure 5

One of the mechanisms involved in psychiatric disorders is considered to be the regulation of gene transcription. Transcription factors, for example, nuclear factor kappa B (NF-κB), and cAMP response element-binding protein (CREB) have parts to play in different processes of the brain which may be dysregulated in schizophrenia patients, like synaptic plasticity, synapse regulation, neurogenesis, and neural migration.

GPCR Dimerization

Figure 6

G protein-coupled receptors (GPCRs) were expected to function as monomers. This model of receptor signaling is reinforced by the observation of G protein coupling via a single purified class A GPCR, like the adrenergic β2 receptor. Yet, it has been shown that class C GPCRs, for example, GABAB  and mGlu receptors, act as dimers.

Furthermore, more recent findings reinforce the hypothesis that family A GPCRs form heterodimers or oligomers of an even higher order. Some examples of GPCR heterodimers/ heteromers, which are potentially connected to schizophrenia and its treatment, include dopamine D2-adenosine A2A, 5-HT2A-mGlu2, d and µ-opioid-α2A-adrenergic receptor complexes.

Epigenetic Targets

Figure 7

Depending on the type of modification, covalent modifications of the N-termini of histones correspond with closed or open states of chromatin. Acetylation (A) of histone H3 (H3ac) and histone H4 (H4ac) forms a more open chromatin architecture.

Histone acetylation is catalyzed by histone acetyltransferases (HATs), and this alteration can be reversed by using the enzymatic action of histone deacetylases (HDACs), which can be split into four different phylogenetic classes.

Discoveries in preclinical models indicate that HDAC inhibitors could arise as a new pharmacological method to treat cognitive deficits in schizophrenia patients.

References and Further Reading

  • Gaitonde and Gonzalez-Maeso (2017) Curr.Opin.Pharmacol. 32 23
  • Hanks and Gonzalez-Maeso (2013) ACS.Chem.Neurosci. 4 33
  • Holloway and Gonzalez-Maeso (2015) ACS.Chem.Neurosci. 6 1099
  • Ibi and Gonzalez-Maeso (2015) Cell.Signal. 27 2131
  • Kurita et al (2016) Novel Targets for Drug Treatment in Psychiatry. In: Fatemi and Clayton eds. The Medical Basis of Psychiatry. Springer, New York
  • Moreno and Gonzalez-Maeso (2013) Int.J.Neuropsychopharmacol. 16 2131

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Last updated: May 20, 2020 at 9:01 AM


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