A recent study has revealed underlying genetic mechanisms behind some of the shared cognitive impairments in both autism spectrum disorder (ASD) and schizophrenia.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic influence. ASD is believed to occur due to complex interactions between many genes and the environment, but because great variation is observed in behaviour-related symptoms, determining the single most important genetic risk factor is extremely difficult.
Schizophrenia is a complex psychotic disorder that tends to run in families. It has been recognised that a combination of many genes is responsible for the condition, each conferring a small increase in liability to the illness. Although it is extremely difficult to pinpoint these susceptible genes, studies on candidates are making progress.
Historically, studies have showed that several of the gene variants linked to ASD and schizophrenia are highly expressed in the thalamus. However, the potentially shared biological mechanisms behind these disorders have not been yet established. The thalamus is a small structure within the brain that plays a role in cognitive tasks, including memory formation and learning. Therefore, common cellular processes identified in ASD and schizophrenia could provide grounds for exploring the possibility of therapeutic approaches for both disorders.
Genes linked to ASD and schizophrenia
Recently, researchers at Massachusetts Institute of Technology (MIT) conducted a series of studies to uncover common neural mechanisms for cognitive impairments seen in ASD and schizophrenia patients. They focussed on the anterodorsal (AD) thalamus, part of the anterior thalamic nuclei (ATN) complex, which is a relatively understudied section of the brain.
Firstly, the team investigated a gene called PTCHD1. The knockdown of PTCHD1 in neurons of the AD thalamus in mice, using CRIPSR-Cas9, resulted in a large deficit in memory encoding. Notably, PTCHD1 mutations have already been established in ASD and are suspected to account for around 1% of patients with neurodevelopmental disorders. The researchers then investigated four other genes – an ASD risk gene called YWHAG and three genes linked to schizophrenia called GRIA3, CACNA1G and HERC1. The knockdown of each of these genes also led to memory deficits.
Additionally, the researchers demonstrated that each of the risk genes for both disorders affected ion channels influencing the firing rate of neurons. Each mutation led to an increase of neuron excitability and circuit-level dysfunction, subsequently presenting as behavioural symptoms. Interestingly, it was found that normal cognitive function in mice with risk gene mutations could be restored by artificially turning down the hyperactivity of neurons in the AD thalamus.
Neuropsychiatric therapies focussed on risk genes
This study highlighted many ASD and schizophrenia risk genes that are expressed in the AD thalamus and can cause cognitive impairments, such as memory deficits. Perhaps the most exciting discovery is the important connection between mutated risk genes for these disorders and hyperactivity of neurons in the ATN. This newfound knowledge could encourage the development of therapeutic strategies, aimed at reducing the hyperactivity of neurons in the AD thalamus, used to treat cognitive impairments in multiple disorders.
Guoping Feng, a professor at MIT, explained: “This study reveals a new circuit mechanism for cognitive impairment and points to a future direction for developing new therapeutics, by dividing patients into specific groups not by their behavioural profile, but by the underlying neurobiological mechanisms.”
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