Table 2.

Biological hypotheses of schizophrenia

Description	Selected reviews	Relevance to sleep and plasticity
Neurodevelopmental hypothesis
Disturbances during critical periods of brain development results in lesions that produce the symptoms of schizophrenia. Disturbances could result from genetic or environmental factors.	Fatemi and Folsom (2009), Rapoport et al. (2012)	Slow waves and spindles reflect and participate in cortical maturation Slow wave and spindle deficits may indicate aberrant neural development Disruption of thalamocortical system during development would lead to impaired slow wave- and spindle-mediated plasticity
Dysconnection hypothesis
Abnormal modulatory activity of neurotransmitters including DA, ACh, and 5-HT results in altered regulation of NMDA-receptor-mediated plasticity. The resulting abnormal functional integration between brain regions gives rise to symptoms of schizophrenia.	Stephan et al. (2009)	NMDAR inactivation may disrupt thalamocortical oscillations, leading to spindle and slow wave deficits that would impact sleep-dependent memory processes
Dopamine hypothesis
Multiple environmental and genetic factors lead to increased presynaptic striatal dopaminergic function. Dysregulation of dopamine-driven circuits of stimulus salience and reward lead to the positive and negative symptoms of schizophrenia.	Howes and Kapur (2009)	D4 receptor excess could disrupt circadian signaling and thalamocortical oscillations COMT SNP shows impaired memory and altered responses to sleep-suppressing agents
NMDAR hypofunction hypothesis
NMDAR antagonists produce schizophrenia-like symptoms in humans and animals, leading to the hypothesis that NMDAR hypofunction is a core pathological mechanism of schizophrenia. This hypofunction impacts other neurotransmitter systems and may result from genetic and non-genetic factors early in life.	Gilmour et al. (2012), Olney et al. (1999)	Hypofunction of NMDARs on TRN neurons would reduce reticular inhibition of thalamocortical neurons and lead to cortical hyperactivity, giving rise to disrupted plasticity and psychotic symptoms
Genetic hypotheses
A single genetic cause of schizophrenia is unlikely. Genetic hypotheses propose polygenic inheritance patterns, post-fertilization mutations due to genetic or epigenetic factors, or some combination of these.	Kim et al. (2011), Owen (2012)	COMT regulates DA levels, which impact sleep-dependent plasticity in the PFC and TRN Flies expressing DISC1 show altered sleep duration. During neurodevelopment, DISC1 is expressed in the TRN, which generates sleep spindles

ACh acetylcholine; COMT SNP catechol-o-methyl transferase single nucleotide polymorphism; DISC-1 disrupted-in-schizophrenia-1; DA dopamine; 5-HT serotonin; NMDAR N-methyl-D-aspartate receptor; PFC prefrontal cortex; TRN thalamic reticular nucleus