While comparable neuronal phenotypes, particularly aberrant dendritic arborization, synaptic density and neuronal migration, are shared between ASD, SCZD and BD, these cellular phenotypes likely result in vastly different network effects in each disorder. Functional imaging facilitates the study of the abnormal neural circuitry behind cognitive dysfunction.
One hypothesis concerning ASD is that short-distance over-connectivity in the cortex leads to a failure of long-distance coupling.79
This hypothesis predicts that impaired long-distance connectivity in the cortex impedes information integration across diverse functional systems (emotional, sensory, autonomic, memory). Consistent with this prediction, fMRI studies of resting state brain activity have observed increased connectivity between proximal regions, such as the posterior cingulate and the parahippocampal gyrus,80
and decreased connectivity between the distal regions, such as the frontal cortex and the parietal lobe,81
the insular cortices and the somatosensory cortices or amygdala,82
the frontal cortex and the posterior cingulate,80
as well as decreased interhemispheric synchronization.83
Comparable defects in long-distance connectivity were found when ASD patients performed social and introspective tasks.84
Among ASD patients, a negative correlation exists between functional connectivity in these regions and severity of social and communication impairment.80, 82
Just as pathological studies of SCZD reported decreased frontal and temporal lobe volumes, early fMRI studies of SCZD patients revealed brain activity abnormalities in the frontal and temporal lobes.85, 86
More recent studies have further shown that SCZD patients exhibit cortical hyper-activity and hyper-connectivity of the prefrontal cortex at rest, but reduced activation of the medial prefrontal cortex during working memory tasks.87
While functional connectivity of the parietal cortex to the ventral prefrontal cortex is greater in SCZD, it is reduced to the dorsal prefrontal cortex.88
This is consistent with anatomical neuronal network maps, which reveal a loss of network ‘hubs’ in the frontal cortex, and increased connection distance. These network aberrations are thought to result from neurodevelopmental abnormalities impacting cortical organization.89
Although fMRI studies can reveal regions of the brain with aberrant activity in the disease state, they cannot elucidate the specific neuronal cell types affected. Therefore, pharmacological and post-mortem studies have generated hypotheses concerning the cell types affected by SCZD. Similar studies of ASD and BD have been less successful in identifying the specific cell types relevant to disease.
Good evidence now links aberrant neurotransmitter signaling to SCZD. Dopamine receptor antagonists reduce the symptoms of SCZD and evidence now links SCZD with increased dopamine receptor levels and sensitivity.90, 91
Comparably, glutamate-blocking drugs such as ketamine produce symptoms generally associated with SCZD,92
whereas the glutamate receptor2/3 agonist LY2140023 may ameliorate the symptoms of SCZD.93
Post-mortem studies of SCZD brains have found decreased glutamate receptor expression,94
whereas among GABAergic interneurons, a decrease in GAD67 and calcium-binding proteins was found. Changes in GABAergic neurons are particularly relevant as they are thought to produce gamma oscillations, which synchronize pyramidal neuron firing, an activity that is impaired in SCZD. Evidence in mice suggests that SCZD results, at least in part, from reduced excitatory glutamatergic input onto GABAergic inhibitory neurons.60, 95, 96
It remains unclear whether aberrant dopamine, glutamate or GABA signaling is the primary cause of SCZD, as aberrant activity of any neuronal cell type could affect neurotransmitter activity of the remaining cell types in the disease state.
In model organisms from Drosophila
to mice, genes associated with ASD, SCZD and BD have been shown to regulate synaptic activity and plasticity. For example, a screen in Drosophila
for genes critical in maintaining homeostatic modulation of synaptic transmission identified the SCZD gene Dysbindin
acts presynaptically, in a dose-dependent manner, to regulate adaptive neural plasticity.97
mice, although synapse formation, elimination and strengthening are normal, the experience-dependent phase of synapse remodeling is impaired98
mice show altered activity-dependent neural gene expression.99
-null mice, lacking a gene associated with ASD, have reduced GABAergic neurons and decreased neuronal synchrony.100
mice have reduced hippocampal synaptic transmission.42, 43Nrg1
mice have impaired synaptic maturation and function58, 60, 61, 62, 101
and 22q11.2 mice show altered short- and long-term synaptic plasticity as well as calcium kinetics in CA3 presynaptic terminals. Defects in synaptic plasticity at the cellular level likely contribute to the network aberrations observed in psychiatric disorders.
One characteristic network defect observed in SCZD is prepulse inhibition (PPI). PPI is a measure of sensory gating, in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). Deficits in PPI are observed in Nrg1
and are reversed by dopamine receptor antagonists.102, 103
mice display not only decreased PPI but also reduced evoked γ-activity, a second pattern seen in patients with SCZD.104
In humans, polymorphisms in circadian genes such as CLOCK
convey risk for BD; mutant Clock
mice also have dysfunctional γ-activity across limbic circuits, which can be improved by chronic lithium treatment.46
While PPI is attributed to glutamatergic activity, reduced γ-activity indicates abnormal GABAergic neurotransmission. Therefore, although pharmacological evidence implicates dopaminergic and glutamatergic neurons in SCZD, network analysis reveals defects in both glutamatergic and GABAergic activity in SCZD and BD. Aberrations originating in any one neuronal subtype would ultimately be expected to affect activity in other types of neurons and in a variety of brain regions. The ability to test synaptic activity in defined populations of human glutamatergic, GABAergic and dopaminergic neurons affected by ASD, SCZD or BD might help to elucidate the neuronal subtypes at the core of each disorder.