| Abstract |
Schizophrenia constitutes one of the most complex psychiatric diseases. Its clinical manifestations
emerge through disturbances in diverse cognitive domains, covering for a wide range of human
mental activity. Eugen Bleuler, a leading exponent of the association psychology of the 19th century,
introduced the term “schizophrenia”, and conceptualized the disease, as a “splitting/ fragmentation
of psychic functions”. This influential concept of disruption of the, normally, unified cognitive
processes, has been adopted and enriched by contemporary theoretical cognitive models, trying to
interpret the pathophysiology of this disease.
Linking the symptoms of schizophrenia with their underlying pathophysiological mechanisms, is
extremelly challenging, as it necessitates the delineation of high order-cognitive functions’ neural
substrate. This study, begins with a theoritical account of the impaired brain processes, underlying
the emergence of SCZ symptomatology and a review of the supporting evidence. A symptom-based
approach, is suggested as a methodology of studying complex psychiatric diseases pathophysiology
and the reasons for which, working memory deficits, are on focus is explained.
The occurrence of schizophrenia, has been associated with a variety of distinct genetic and
environmental risk factors, but in the last years, the genetic component of the disease has been on
the scene. The continuously expanding, genetic findings of Genome Wide Association Studies,
provide us with associations of SNPs in multiple genes, with susceptibility risk. SCZ related genes,
encode for proteins, previously implicated in the pathophysiology of the disease. In this context,
SCZ-associated SNPs in CACNA1C gene, which encodes for the L-type Ca2+ ,Cav 1.2 channel,
appears to be one of the most consistent findings.
The prevalent role of prefrontal cortex, in the mediation of cognitive functions is underlined and the
implication of its impairement in the pathophysiology of SCZ, is extensively argued. PFC’s
segregation in functional subdivisions, on a large-scale level, is depicted with an overview of its
functional and structural connectivity. Furthermore, its functional segregation, on a between and
intra-layer level, is inferred by presenting evidence, which suggest the formation of subcircuits with
distinct, regarding their features, pyramidal neuronal populations.
Working memory, is a cognitive function, mediated predominantly by the neural substrate of PFC. Its
impairement is a concistent finding in SCZ and lately, is associated with the presence of SCZ-related
SNPs. The cellular correlate of working memory, persistent activity, is mainly observed in prefrontal
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pyramidal neurons and it is considered, an emergent property of their incorporation in networks.
From the relevant literature review, we picked out evidence, suggesting that this network property is
differentially mediated by distinct, pyramidal subpopulations, in the context of normally specialized
brain function. The first question that arises, concerns the specific way these subpopulations
contribute to the induction, maintenance and stimulus-selectivity of this network property. An
attribute of normal brain specialization is the documented differentiation of intrinsic excitability of
prefrontal, pyramidal neurons. This brings us to the second question; is this differentiation of
intrinsic excitability and its consequent impact to the emergent network function, a common
attribute between normal, brain specialization and the kind of pathologic state, imposed by the
functional effects of SCZ-related SNPs?
We undertook a computational approach to study whether, the firing-pattern specific PFC
subcircuits and CACNA1C variants of these subcircuits, exhibit differentiated properties of
persistent activity.
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