March 4, 2019, by hjohnson
Altered gene expression in neurotransmitter pathways observed in Schizophrenia
Written by Vaishali Gursal (3rd year BSc Neuroscience)
Schizophrenia is a severe, long-term debilitating neuropsychiatric disorder whereby an individual is unable to separate their own thoughts from reality. The exact causes of schizophrenia are unknown, although environmental and genetic factors combined can enable susceptibility to trigger the condition. Positive and negative symptoms of the mental condition can arise. Positive symptoms are those that are not normally present in healthy individuals, such as auditory and visual hallucinations and delusions, which can be treated moderately effectively with antipsychotic medication. However, negative symptoms involving a loss of normal function, such as a decline in mental processes required to carry out daily tasks, depression, severe lack of engagement in daily life (managing personal relationships, keeping a job, caring for health and personal appearance), and are far less responsive to current therapies. Current antipsychotics block dopamine D2 receptors, hence preventing dopamine, a neurotransmitter in the central nervous system, from binding and exerting its motivational and reward-motivated effects. These therapies effectively target the positive symptoms of schizophrenia but have limited benefits against the negative and cognitive deficits that are observed1. Research into how potential drugs may target neurotransmitter pathways to treat negative symptoms of schizophrenia is ongoing.
An anticonvulsant drug called lamotrigine, which has been prescribed to treat epilepsy and bipolar disorder, has been known to block the conduction of sodium ions through sodium channels, preventing neurons from conducting action potentials (electrical signals) and reducing the release of excitatory neurotransmitters. This inhibits cell to cell communication. However, lamotrigine has not been approved to treat schizophrenia as more robust and extensive testing in schizophrenia models is required. Hopefully, along with epilepsy and bipolar disorder, it may also be prescribed to treat schizophrenia in the future because it has been shown to decrease cognitive impairments in clinical models, possibly due to modulating glutamate (an excitatory neurotransmitter) release in the cortex of the brain. Lamotrigine may even be prescribed in combination with other antipsychotic drugs, such as clozapine, that also act on glutamate and dopamine neurotransmission in order to increase the inhibition of glutamate to treat schizophrenia more effectively.
Several neurotransmitter systems and processes are implicated in schizophrenia, particularly dopamine, glutamate (the primary excitatory neurotransmitter with a role in learning and memory), and GABA (the primary inhibitory neurotransmitter with a role in anxiety, motor control and vision). A study was conducted by the University of Nottingham, led by Dr Kevin Fone, Dr Stephen Alexander and Dr Maria Toledo-Rodriguez observing the alterations in neurotransmitter signalling pathways of dopamine, glutamate and GABA and examining the ability of lamotrigine, a sodium channel blocker, to reduce schizophrenia behavioural deficits.2 Additionally, the changes in hippocampal (the memory centre of the brain) neurotransmitter-related gene expression with those reported in schizophrenia were analysed using DNA microarray, a tool used by scientists whereby DNA spots are present on a plate and is used to measure the expression levels of genes or to determine any mutations that have occurred within the genome.
It was found that alterations in gene expression occurred in three key neurotransmitter pathways, glutamate, dopamine and GABA, which are all relevant to the development of schizophrenia. Lamotrigine also significantly reduced hyperactivity in clinical models of schizophrenia. It disrupted the signalling mechanisms that are coupled to D2 dopamine receptors, hence directly interfering with dopamine signalling and reducing hyperactivity. However, lamotrigine is not completely useful in restoring cognitive deficits and improving working memory performance.
In schizophrenia models, an alteration in expression of genes involved in cell survival and apoptosis (cell death) was observed when DNA microarrays of the prefrontal cortex were analysed. A decrease in the level of brain derived neurotrophic factor (BDNF – enables survival and growth of neurons) and development related genes in the prefrontal cortex and dentate gyrus of the hippocampus was seen. It was found that the gene encoding the dopamine D5 receptor was downregulated, meaning that dopamine cannot exert its effects through this receptor. Additionally, the 1.24-fold decrease in the gene which encodes the synthesis of dopamine means that there is less dopamine available in the system, which has been associated with the age of onset of schizophrenia in male patients. Genes encoding proteins involved in the metabolism of glutamate were also affected in schizophrenia models. Additionally, a gene encoding the synthesis of GABA was found to be downregulated in both the hippocampus and cortices of clinical models, meaning that a decrease in GABA release may have caused a reduction in hippocampal plasticity and function, resulting in cognitive deficits that are observed in schizophrenia.
DNA microanalysis has identified the convergence and interaction of different neurotransmitter pathways and how these are affected in schizophrenia. Genome-wide association studies reveal that thousands of common single nucleotide polymorphisms exist, whereby there are small changes in the DNA sequence, but each has a very small effect on the development of schizophrenia, only cumulatively explaining around 30% of the genetic component of the condition.
Schizophrenia is a complicated condition because it is caused by a summative interaction of multiple neurotransmitter pathways, which causes a range of positive and negative symptoms to be seen. The management and treatment of schizophrenia can be improved by further establishing which genes are involved and which drugs, either singularly, or in combination, can be administered to treat the varied symptoms, both cognitive and physiological, that are characterised in schizophrenia. This study is important in identifying a few genes whose function is affected in this condition, although further experimentation is needed to identify the extent to which these genes manifest the condition and what mutations are observed, so that in future, changing the DNA sequence using gene therapy could potentially be explored. While currently most anti-psychotic drugs target the dopamine neurotransmitter pathway in order to increase the effects of dopamine within the system, in the future, research into facilitating GABAergic activity and targeting voltage-gated sodium channels could reveal a mechanism through which therapeutic drugs can act in order to restore the neurotransmitter balance in the central nervous system and reverse cognitive deficits observed in schizophrenia.
References and further reading:
[1] https://www.nhs.uk/conditions/schizophrenia/
[2] https://academic.oup.com/ijnp/article/19/11/pyw062/2629246
Gaskin PL, Toledo-Rodriguez M, et al (2016) Glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia. Int J Neuropsychopharmacol. 19(11)
Photo by David Cassolato from Pexels
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