Let us assume, without taking ourselves too seriously, that schizophrenia is caused fairly late in neurodevelopment by a misspecified gene product
(1). Now, assume that this product is necessary for molecular signaling or interactions between subunits of the
N-methyl-
d-aspartic acid (NMDA) receptor and one or more receptor subtypes that mediate cholinergic and dopaminergic neurotransmission (e.g., reference
2). How might this be expressed phenotypically? The NMDA receptor has a central role in activity or experience-dependent plasticity. However, our genetic abnormality does not affect NMDA-receptor function directly, only its modulation by cholinergic or dopaminergic neurotransmission. What is the functional importance of this modulation? Theoretical neurobiology offers two answers. The first and more established comes from theoretical models of reinforcement learning (e.g., temporal difference models and dynamic programming). The second derives from ideas about how the brain encodes uncertainty about its perceptual constructs. Critically, both posit a central role for acetylcholine and dopamine in enabling changes in synaptic efficacy. In reinforcement, or emotional learning, the notion is that dopamine encodes predicted reward and can be used to consolidate synapses mediating stimulus-response links of high value (e.g., reference
3). The second set of ideas deals with perceptual learning and suggests that acetylcholine encodes uncertainty about perceptual inferences
(4). Mathematical treatments of perceptual learning
(4,
5) confirm the intuition that associative plasticity should be greater when conditional certainty is high.
In short, normal interactions between dopamine and the cellular or synaptic mechanisms responsible for plasticity are essential for emotional learning, whereas the interaction between cholinergic neurotransmission and associative plasticity is important for perceptual learning. See also Barch
(6), who considers working memory from a pharmacological perspective and concludes, “compounds geared towards enhancing the dopamine system and the acetylcholine system remain promising avenues for the development of pro-cognitive drugs.”
The hypothetical genetic abnormality mentioned is special because it targets experience-dependent plasticity induced by emotional and perceptual learning. This means it is a genetic abnormality that can only be expressed through the phenotype’s interaction with the world. This fits comfortably with the stress-diathesis model of schizophrenia. If schizophrenics were unlucky enough to encounter situations that called for emotional or perceptual (re)learning (e.g., life events or a researcher with a perceptual learning paradigm), they would be compromised. This would be expressed, at a synaptic level, as abnormal connectivity leading to a disintegration of neuronal dynamics underlying response selection and perception. This is the disconnection hypothesis
(7). The ensuing functional consequences would be expressed as an inability to form new stimulus-response links (impaired emotional learning) or stimulus-stimulus links (impaired perceptual learning). In terms of cognition, this could be expressed as cognitive dysmetria
(8) and, at lower levels, a disruption of perceptual learning and inference (i.e., perceptual dysmetria). With this theoretical framework in place, we can now preview the main findings in this issue’s articles.