More Than Molecules: A Circuits Approach to Schizophrenia

Part 1: The Mesolimbic Pathway

Written by: Desiree Lano

Image credit: https://www.cedars-sinai.org/newsroom/wired-for-life-study-links-infants-brain-circuitry-to-future-health/

To the layperson, dysfunction of dopamine (DA) has long been considered a major contributor to the pathophysiology of schizophrenia (SCZ). The reality, however, is far more complicated. Enter: glutamate (Glu). As the brain’s main excitatory neurotransmitter, Glu is essential for numerous functions in the brain, including but not limited to learning; memory; and neuroplasticity (Dwyer 2024). In fact, over 80% of our synapses are classified as glutamatergic. While Glu is vital for normal brain function, excessive glutamatergic activity can ultimately lead to excitotoxicity (damage to the nervous system due to excessive activity), which is implicated in various psychiatric and neurodegenerative diseases (Lee 2024). Unsurprisingly, Glu dysfunction has been found to be just as implicated as DA when it comes to the development and progression of SCZ. This article will give a short, easy-to-digest review of what is currently known about the relationship between Glu and DA in the pathology of SCZ and how this can inform current and future treatment. (P.S.: if you’re unfamiliar with the symptoms of SCZ, feel free to refer to my former article here for a primer.)

To understand Glu’s contributions to SCZ, we need to start at one of its primary targets: the N-methyl-D-aspartate receptor, or NMDAR. The NMDAR is not necessarily the sole impetus for neurotransmitters going haywire (that is a whole other, even more complicated, topic), but it is certainly the easiest place to start. The core function of NMDARs in the brain is to receive a single message from Glu: “Go!” Now, whether that signal ultimately leads to the neuron firing depends on the cumulative input of all the other receptors involved and their signals. Still, this is an important concept to keep in mind when we discuss how the glutamate system is involved in SCZ.

Here’s a quick snapshot of what’s happening in the circuit: pyramidal glutamatergic neurons initiate the pathway in the frontal cortex. These neurons synapse onto GABA interneurons also in the frontal cortex. GABA can be thought of as Glu’s counterpart—while Glu excites, GABA inhibits. The way the brain interprets these two opposing signals is a bit like how a computer processes binary code: it’s not the individual 0s and 1s that make the message, but the combination of signals that determine a neuron’s output). This stimulation of the GABA interneuron, and the subsequent release of inhibitory GABA neurotransmitter onto the next pyramidal glutamatergic neuron, keeps the glutamatergic neuron “in check” so to say. Without this GABA interneuron keeping tabs on the glutamatergic neuron, said neuron will become overexcited and fire excessively. Given that this glutamatergic neuron projects into the midbrain VTA onto DA neurons, this overexcites the DA neurons that lead to the striatum, ultimately leading to an overabundance of DA in this area. (Buck et al. 2022) This circuit is called the “mesolimbic pathway”, one of the primary dysfunctional circuits implicated in schizophrenia. So, while DA is undeniably involved, its interaction with Glu reveals a more intricate story .

So, how did this hypothetical model come to light? Believe it or not, it started with PCP and ketamine. Originally used clinically–and recreationally–as dissociative anesthetics, these drugs were observed to produce symptoms indistinguishable from positive and negative symptoms in schizophrenia. Researchers then found the mechanism of action explaining the  effects of the drug: blockade of the NMDAR (Kruse et al. 2022). The blockade in this case was thought of as an “induced” hypofunction of the NMDAR. It was hypothesized to be the cause of SCZ symptoms, and evidence supporting the hypotheses for these claims emerged soon after, with many similarities observed between chronic blockade of the NMDAR in animal models using PCP or ketamine and post-mortem brains of patients with SCZ (Kruse et al. 2022).

To summarize: while excessive DA release is certainly implicated in the symptomatology of SCZ, it is not an isolated phenomenon. Glu is the troublemaker, and DA is the scapegoat. There is also the additional problem of excessive Glu leading to excitotoxicity and even more severe symptomatology as neurons die off. No wonder SCZ is so difficult to treat! While atypical antipsychotics have contributed greatly to lessening the more severe symptoms of SCZ, there is still a continued need for research aimed at  developing a more fine-tuned approach to treating the disease.

This article has provided a fairly high-level overview of the interplay between Glu and DA in the pathophysiology of schizophrenia. Stay tuned for part 2 where we will explore Glu’s involvement in the mesocortical pathway–a key circuit whose dysfunction leads to the negative and cognitive symptoms of SCZ. For more detailed information, please consult the cited literature below.

References

Buck, S. A., Quincy Erickson-Oberg, M., Logan, R. W., & Freyberg, Z. (2022). Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia. Molecular Psychiatry, 27(9), 3583–3591. https://doi.org/10.1038/s41380-022-01649-w 

Dwyer, G. E., Johnsen, E., & Hugdahl, K. (2024). NMDAR dysfunction and the regulation of dopaminergic transmission in schizophrenia. Schizophrenia Research, 271, 19–27. https://doi.org/10.1016/j.schres.2024.07.025 

Kruse, A. O., & Bustillo, J. R. (2022). Glutamatergic dysfunction in schizophrenia. Translational Psychiatry, 12(1). https://doi.org/10.1038/s41398-022-02253-w 

Lee, H.-J., Kim, H.-Y., Oh, S. J., Son, Y., Kang, K. J., Nam, K. R., & Choi, J. Y. (2024). Administration of aripiprazole alleviates memory impairment and restores damaged glutamatergic system in 5xfad mice. Molecular Imaging and Biology, 26(5), 879–887. https://doi.org/10.1007/s11307-024-01944-8