The glutamate model of psychosis

The glutamate receptor in patients with schizophrenia

According to Prof Moghaddam, there is a deadlock in treatment for schizophrenia as there is still limited understanding of the underlying pathology. The use of animal models is one way to aid this understanding and test specific mechanistic hypotheses. Such models can be used to build a picture first of aetiology, then pathophysiology, then specific symptoms. However, modelling schizophrenia in animals is complicated as the temporal dynamics of the condition are hard to replicate.¹

Cortical processing in patients with schizophrenia is linked to glutamate-led dysfunction

Cortical processing, dominated by glutamate-led neurotransmission, is dysfunctional in patients with schizophrenia.^2,3 The glutamate synapse has a large number of drug targets⁴ and electrophysiological studies in the rat prefrontal cortex following administration of phencyclidine (PCP), ketamine or MK801 found that they lead to profound excitation.^5,6 This helped Prof Moghaddam’s laboratory identify metabotropic Glu2/3 (mGlu2/3) receptor as a target⁶ and led to clinical trials of mGlu2/3 receptor activating drugs. Results showed that 4 weeks treatment led to a 32% decreases in PANSS total scores. This was similar to the 40% decrease with olanzapine, but the mGlu2/3 agonist was not associated with extrapyramidal symptoms, weight gain or prolactin elevation.⁷ However, while overall large Phase III trials did not replicate results, significant improvements were shown in patients with early disease,⁸ meaning, according to Prof Moghaddam, this may be the best time to intervene with such a drug.

Genetic factors in schizophrenia

Studies also point to a role of ionotropic N-methyl-D-aspartate glutamate (NMDA)  receptor subtypes.^3,9 Large scale genomic studies show convergence of both common and rare variant associations related to a handful of genes in patients with schizophrenia.^10,11 For instance, the GRIN2A gene, which codes an NMDA receptor subunit called GluN2A, has been identified as having a role in moderate to substantial disease risk, depending on the variant.^10,12 While there is little to no GluN2A expression at birth, this evolves over the first couple of years of life to adult levels.¹³ Prof Moghaddam proposed, therefore, that schizophrenia symptoms related to GRIN2A loss of function would not evolve until the pre-adolescence/adolescence period when adult levels are being reached. She presented work carried out in her laboratory that showed that in rats, levels of GluN2A remained stable over the adolescent developmental period (from Day 21) in the medial prefrontal cortex, hippocampus, dorsal striatum and nucleus accumbens (Kielhold et al, unpublished).

Genomic studies shown a number of genes related to schizophrenia

Modelling deficits in schizophrenia in animals

Also shown in schizophrenia is the emergence of dopaminergic abnormalities in adolescence, correlating with positive symptoms and early psychosis.^14,15 Dopamine neurons are located in the substantia nigra (SN) and ventral tegmental area (VTA). Prof Moghaddam colleagues’ work found that in contrast to the regions discussed above, there was a significant decrease of GluN2A in development in these areas in rats (Kielhold et al, unpublished). This may explain, she postulated, why dopamine-related positive symptoms of schizophrenia do not emerge until later adolescence. This has been replicated in a GRIN2A knockout (KO) rat where, during early adolescence, targeting VTA and SN dopamine neurons using Cre-driven CRISPR generated viruses led to decreased expression and loss of function of GluN2A. In this model, no gross behavioural differences were found in baseline locomotion and simple reward-guided associated learning was not affected (Kielhold et al, unpublished); however, other behaviour that may represent abnormalities of perceptual organisation was shown.

Dopamine-related positive symptoms of schizophrenia usually emerge in later adolescence¹

In the progressive ratio task, an animal has to respond to a stimulus with an action but the number of times needed to respond before obtaining a reward progressively increases. During this task, wild-type (WT) rats exhibit a post-reinforcement pause where they stop for longer time periods before obtaining their reward as the ratio requirement increases. This is proposed to be a period when the animal is assessing whether the effort is worth the reward. The KO rats have a large reduction in the pause, which Prof Moghaddam postulated to be due to impaired perceptual organisation (Kielhold et al, unpublished). This could, she said, be due to a lower influence of the context, problems in optimising the allocation of effort and/or a decrease in the ability for behaviour to be influenced by negative feedback.

In a Pavlovian task, a tone was linked to a reward and light to a shock. Once a rat has learnt this, the contingencies are switched. In WT rats, when a stimulus starts as aversive and is switched to rewarding, they gradually reward seek more, but with hesitancy compared to when the initial stimulus is rewarding. In KO rats, while they do learn to avoid the aversive stimulus, as soon as it shifts to reward, they quickly learn to react to it, without the hesitancy seen in WT rats (Kielhold et al, unpublished). This was proposed by Prof Moghaddam to be due to impairments in the ability to use feedback or mental representation to guide behaviour or to faulty inference and evidence accumulation. This may reflect findings in patients with schizophrenia.¹⁶

Currently, positive allosteric modulators of NMDA receptors containing GluN2A are being investigated.¹⁷ If these type of medications are shown to be safe for human use, Prof Moghaddam postulated that these could be used in an animal mode to discover and screen treatments for positive symptoms.