Rethinking schizophrenia in the context of normal neurodevelopment

Abstract

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis.

Keywords: GABA receptor; NMDA receptor; cognition; dopamine receptor; excitatory synapses; myelination; neural migration; neurogenesis.

Figure 1

Normal developmental trajectory of cognitive executive function. The trajectory of cognitive executive functioning development is derived from developmental tables in the Wisconsin Card Sorting Manual [modified from Heaton et al. (1993)]. The other trajectories correspond to the spectral power in gamma bands during a face recognition task (30–75 Hz, all electrodes; Uhlhaas et al., 2009) as well as cumulative increments in computer quantified changes in EEG frequency spectrum (QEEG) between fronto-temporal cortices, derived from Hudspeth and Pribram (1990).

Figure 2

Normal developmental trajectory of neurogenesis, neuronal migration, and myelination in the human. Neurogenesis and the subsequent migration of neurons to the cortex begin within a few weeks of gestation in the human (Zecevic et al., 2011). Pyramidal neurogenesis and migration of these cells to the cortex occurs by radial migration and is completed by mid-gestation (Nadarajah and Parnavelas, 2002), while genesis and migration of GABAergic interneurons continues into early post-natal life, with emerging evidence based on the presence of molecular markers of immature neurons suggesting that this process continues into adulthood in primates (Gould et al., , ; Bernier et al., ; Fung et al., ; Wang et al., 2011). Prefrontal myelination occurs predominantly in early post-natal life, still increasing through adolescence before reaching adult levels (Kang et al., 2011).

Figure 3

Normal developmental trajectories of expression of inhibitory system components in the human prefrontal cortex. Normal development of GABA receptor components of the inhibitory system is dynamic until adolescence where the trajectories reach a steady or declining state. GABA_A (GABR_A) subunits display two distinct patterns, one of decreasing expression following birth (α2, α5, β1, γ1, γ3 subunits) and a M pattern (dynamic expression) with peaks at toddler and teenage time periods (α1, α4, β2, β3, γ2 subunits; Fillman et al., 2010). The peak in the ratio of GABA α1 to α2 subunits (GABRA1/GABRA2) coincides with increased gamma band power in the prefrontal cortex (refer Figure 1). Expression of inhibitory neuron markers display either decline over post-natal life (SST, somatostatin; CR, calretinin; NPY, neuropeptide Y), initial up-regulation and then decline or plateau around school age (CB, calbindin; VIP, vasoactive intestinal peptide), or increased expression over post-natal life (PV, parvalbumin; CCK, cholecystokinin; Fung et al., 2010).

Figure 4

Normal developmental trajectories of excitatory system components in the human prefrontal cortex. Normal development of the excitatory system involves increasing expression of presynaptic SNARE complex proteins (SNAP-25, syntaxin 1A, VAMP1) into early adulthood (Webster et al., 2011) and a similar increase in protein expressions of the post-synaptic markers, PSD95 and spinophilin, though starting at a higher baseline at birth (Kang et al., ; Webster et al., 2011). Dendritic arborization indexed by average length of the total dendritic tree of layer III pyramidal neurons does not reach its maximum until adulthood with a slight decline after the age of 30 years (Petanjek et al., 2008). Quantification of Golgi-impregnated tissue suggests an increase in spine density from birth until early school age, followed by a period of gradually decreasing density starting in early adulthood which lasts until middle age (Petanjek et al., 2011).

Figure 5

Normal developmental trajectories of NMDA receptor subunits in the human prefrontal cortex. Normal development of NMDA receptor subunits (Choi et al., ; Colantuoni et al., ; Kang et al., 2011). mRNA of the obligatory NMDA receptor subunit, GRIN1 (NR1), is expressed at fairly steady levels post-natally, at least until middle age. GRIN2A expression increases in infancy to attain fairly steady levels throughout childhood and then decreases through adolescence and into adulthood. GRIN2B, GRIN2D, and GRIN3A all have their highest expressions at birth with decreasing trajectories thereafter.

Figure 6

Normal developmental trajectories of dopamine and cannabinoid expressions in the human prefrontal cortex. Expression of dopamine receptor, DRD1 suggests an inverted U-shape with increasing expression of receptors until the mid-twenties after which there is a slow decline (Rothmond et al., 2012). The DRD2 isoforms and DRD5 show an inverse pattern, peaking prenatally with a continuous decline in expression throughout life, excepting a small increase in the early twenties (Rothmond et al., 2012). The expression of DRD4 as determined by in situ hybridization is stable across the lifespan (Weickert et al., 2007). Measurement of this receptor by quantitative PCR has been quite variable and no statistical differences in expression across age groups have been detected (Rothmond et al., 2012). Cannabinoid receptor mRNA has its highest measured expression at the time of birth and shows a stepwise decline with age, reaching 30% of maximal expression in middle age (Long et al., 2012).