Converging models of schizophrenia--Network alterations of prefrontal cortex underlying cognitive impairments

Abstract

The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal.

Keywords: Brain imaging; Circuitry formation; Circuitry maturation; Cognitive function; Networks; Oscillation; Prefrontal cortex.

Figure 1. Comparison of the PFC between primates and rodents

The PFC is defined as the frontal cortex that has connections with the MD nuclei of the thalamus. In rodents, the mPFC and ACC are connected with the medial part of MD, whereas the OFC is connected with the lateral part of MD. In primates and humans, the DLPFC and dorsal part of ACC are connected with the lateral part of MD, whereas the ventral part of ACC and OFC are connected with the medial part of MD. Note that in humans, BA24 corresponds to the ventral ACC while BA32 corresponds to the dorsal ACC, and since the areas are concaved anteriorly, BA32 can be seen both superior and inferior to BA24 in this plane of section. BA25, subgenual cingulate, is situated ventrally to these two areas and also more posterior to the plane of section, and cannot be seen. OB: olfactory bulb, CC: corpus callosum.

Figure 2. Maturation of the local circuitry and long rage connectivity

The local circuitry consists of excitatory and inhibitory neurons. A triangle is the cell body of pyramidal neurons, major excitatory projection neurons, whereas a circle is the cell body of inhibitory interneurons. Each local circuit is connected with other local circuits via long range connections that are myelinated. Inputs to the area would affect local circuitry maturation. The inputs would also be affected by the degree of myelination, as the degree of myelination determines the speed of neural transmission, affecting the inputs to the local circuitry.

Figure 3. Developmental profiles of mouse PFC

During development of the mouse PFC, many biological processes take place sequentially. First, a subunit switching for the NMDA receptor component, NR2 takes place, followed by the drastic increase of interneuron marker gene expression during postnatal week 2–4. Slightly delayed is the increase of oligodendrocyte/myelin related gene expression, implicating that myelination process may take place by postnatal week 5. But the PFC is not mature functionally based on the responsiveness to MK801 injection. The response becomes adult like at postnatal week 8. During adolescence (postnatal week 6–8), inhibitory neurons and the neuromodulatory system seem to further mature. Social isolation, an environmental insult, performed during postnatal week 3–5 affects myelin formation, whereas that performed during postnatal week 5–8 affects dopamine synthesis via stress response. Interestingly, the different timing of the treatment results in different behavioral phenotypes later in life (Makinodan et al., 2012; Niwa et al., 2013; Ueda et al., 2015).

Figure 4. What might be happening in the PFC during development/maturation that leads to schizophrenia phenotypes?

Development of neural circuitry/networks that support cognitive functions occurs over decades. If the process proceeds without any issues, healthy network is formed to support everyday life in society. However, several genetic and environmental insults make vulnerable circuitry with somewhat impaired cognitive functions. The vulnerable circuitry, which has unbalanced excitatory/inhibitory activity (E/I), aberrant dopamine (DA) system, and reduced signal to noise (S/N) ratio, can be further impaired by synaptic stress and inflammation during adolescence, resulting in network disturbances and system failure, that lead to the psychosis/onset of the disorder.