Schizophrenia is a disabling mental disorder that affects nearly 1% of the population (Perala et al., 2007
). It is characterized clinically by positive symptoms (psychosis, hallucinations), negative symptoms (social withdrawal, flat affect, anhedonia), and cognitive deficits. One of the over-arching pathologies of this disorder is impaired synaptic connectivity, which has been observed across numerous human post mortem
, as well as functional and structural brain imaging studies (Selemon and Goldman-Rakic, 1999
). The abnormalities in neural connectivity are present in multiple brain regions that are important for regulating cognitive function, sensory processing, and affect.
One of the most consistent structural abnormalities found in schizophrenia is the volumetric reductions of the medial temporal lobe (hippocampal formation, subiculum, parahippocampal gyrus) and of the neocortex (Ross et al., 2006
). In schizophrenia, there is decreased cortical volume (Rasser et al., 2009
) and widespread reduction in cortical thickness, which is most pronounced in the temporal cortex and frontal lobe (Goldman et al., 2009
). Since these volumetric reductions are associated with increased cell packing density, but not changes in neuronal number, they are likely due to decreased amounts of cortical neuropil (the axon terminals, dendrites and dendritic spines, and glial processes that occupy the inter-neuronal spaces) (Selemon and Goldman-Rakic, 1999
). Several lines of evidence support this notion. Post mortem
studies have found changes in cortical molecular markers that suggest that both neuronal and/or axonal integrity are compromised (Bertolino et al., 1996
; Buckley et al., 1994
), and that the number of synapses (Stanley et al., 1995
) is reduced in schizophrenia. In addition, the complexity of dendritic branching, total dendritic length, and dendritic spine density of pyramidal neurons is reduced in the prefrontal cortex (PFC) of patients with schizophrenia (Garey et al., 1998
; Glantz and Lewis, 2000
; Kalus et al., 2000
; Rajkowska et al., 1998
). The number of puncta immunoreactive for spinophilin, a marker of dendritic spines, is reduced in the primary auditory cortex in schizophrenia (Sweet et al., 2008
). As dendritic spines are the principal structural targets of excitatory neurotransmission, these findings suggest that the disruptions in dendritic morphology alter the cortical and/or thalamic circuitry in schizophrenia, which in turn might be the neurobiological substrate underlying the cognitive and sensory dysfunctions observed in patients (Lewis and Gonzalez-Burgos, 2008
Neuroimaging studies have also provided evidence for impaired connectivity in schizophrenia. Functional magnetic resonance imaging (fMRI) has shown abnormalities in the activation of the dorsolateral prefrontal cortex (DLPFC), medial temporal lobe, hippocampus, anterior cingulate, striatum, and thalamus (Niznikiewicz et al., 2003
), which are associated with impaired working memory (Potkin et al., 2009
). Diffusion tensor imaging (DTI), a technique that exploits the directionality of water diffusion, can evaluate the organization and coherence of white matter fiber tracts. These tracts serve as anatomical connections between proximal and distant brain regions, thereby creating functional networks. Deficits in white matter tracts appear to be present in the early stages of schizophrenia, even in neuroleptic-naive patients (Kyriakopoulos and Frangou, 2009
). Although the pattern of abnormalities is not totally consistent across studies, white matter tracts are most affected in frontotemporal, frontoparietal, and temporooccipital connections (Kyriakopoulos and Frangou, 2009
). These imaging results provide further evidence for the presence of structural disconnectivity in schizophrenia.
Schizophrenia has a strong genetic component (heritability of approximately 0.8) as evidenced by family and twin studies. However, the genetics are complex, with no single gene producing a strong effect. Rather, schizophrenia appears to be the result of multiple genes of moderate effect interacting with each other, and the environment, to produce a phenotype (Purcell et al., 2009
). Recent research suggests that highly penetrant de novo
copy number variants (deletions and/or duplications) also contribute to the genetic risk for schizophrenia (Purcell et al., 2009
). Linkage and association studies have now implicated several loci in the genome that appear to contain genes conferring risk to schizophrenia (Ross et al., 2006
). Although initial genetic studies provided suggestive evidence for associations between schizophrenia and putative risk genes, the strength of these associations has recently been called into question as hypothesis neutral genome wide association studies (GWAS) have not confirmed these risk gene associations. However, an important limitation of GWAS is that they examine hundreds of thousands to millions of single nucleotide polymorphisms (SNPs) requiring a substantial correction for multiple comparisons that can compromise statistical power (Cannon, 2010). Thus, there is debate whether negative GWAS findings invalidate the results of candidate gene association studies or that they are insufficiently powered (Cannon, 2010).
Ideally, the evidence for association would come from repeated demonstration of a directional association (even if non-significant), such that pooled- or meta-analyses show a clearly significant directional effect (Norton et al., 2007). However, there have been difficulties in defining what constitutes replication, since many studies vary in their methods, marker sets employed, phenotype definition, and other study design characteristics (Munafo et al., 2008
). In addition, when based upon indirect association, replication of particular alleles may not be easily obtained due to a mixture of population differences in allelic heterogeneity at the locus, allele frequencies, patterns of linkage disequilibrium (LD), phenotypic variation relevant to the associated allele, or exposure to environmental variables with which a risk allele interacts (O’Donovan and Owen, 1999). Association to the same allele across studies should be sought, but it cannot be a pre-requisite for considering a study as supportive of association between disease (i.e. schizophrenia) and a particular gene; instead, it is legitimate to consider association to any allele or haplotype as significant evidence for replication at the gene-level, if it both survives honest appropriate correction for multiple testing and is based on a well-designed quality-controlled study. (Norton et al., 2007).
The purpose of this review is to highlight some of the most studied neuroplasticity pathways implicated in the etiology of schizophrenia, both genetically and biologically, and detail the signaling cascades involved in their regulation of synaptogenesis and plasticity. In addition, this review will discuss how different pathways might converge and how perturbations in these pathways might contribute to the pathophysiology of schizophrenia.