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Bilecki, W.;  Maćkowiak, M. Prefrontal Cortex in Schizophrenia. Encyclopedia. Available online: https://encyclopedia.pub/entry/40879 (accessed on 09 July 2025).
Bilecki W,  Maćkowiak M. Prefrontal Cortex in Schizophrenia. Encyclopedia. Available at: https://encyclopedia.pub/entry/40879. Accessed July 09, 2025.
Bilecki, Wiktor, Marzena Maćkowiak. "Prefrontal Cortex in Schizophrenia" Encyclopedia, https://encyclopedia.pub/entry/40879 (accessed July 09, 2025).
Bilecki, W., & Maćkowiak, M. (2023, February 06). Prefrontal Cortex in Schizophrenia. In Encyclopedia. https://encyclopedia.pub/entry/40879
Bilecki, Wiktor and Marzena Maćkowiak. "Prefrontal Cortex in Schizophrenia." Encyclopedia. Web. 06 February, 2023.
Prefrontal Cortex in Schizophrenia
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This entry is adapted from the peer-reviewed paper 10.3390/genes14020243

Disturbances in cognitive function are crucial symptoms of schizophrenia. Impairments in attention, memory, and executive functions, i.e., the ability to plan, initiate and regulate goal-directed behaviour are present throughout the entire course of the illness. 

schizophrenia transcription epigenetics

1. Prefrontal Cortex Development and Function

The prefrontal cortex (PFC) is the cortical region located in the anterior part of the frontal lobe. Anatomical definitions of the PFC are broadly diversified across species, accounting for various cognitive abilities [1]. Structural and functional homology is used for brain area classifications across species. Primate PFC can be divided into lateral (dorsal and ventral regions), orbitofrontal, medial and cingulate areas. Two major types of neurons create the local circuitry in the PFC: excitatory and inhibitory ones. Excitatory neurons are 70–75% of the neuronal population and use glutamate as the neurotransmitter, while 25–30% are interneurons using γ-aminobutyric acid (GABA) as the neurotransmitter [2]. Interneurons make synapses on definite compartments of pyramidal (excitatory) neurons, and they are divided into subgroups with specific neurochemical, anatomical, physiological and functional characteristics. PFC interneurons have been classified as calcium-binding proteins - parvalbumin (PV) or neuropeptides - somatostatin (SST), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) [3]. The anatomical connections of long-range inputs formed on prefrontal GABA-ergic interneurons are mediated by stimulation of PV and/or SST expressing cells [4]
PV cells are fast-spiking non-adapting neurons, which are divided into basket cells targeting the soma and proximal dendrites of pyramidal cells and chandelier cells targeting the initial axon segment of pyramidal neurons. PV-positive cells are involved in the regulation of optimal excitatory/inhibitory (E/I) balance in the PFC. Inhibitory GABA signalling among PV-positive basket cells and excitatory pyramidal neurons is essential for proper γ oscillatory activity of neurons participating in cognitive phenomena such as working memory and attention [5][6]. Another class of interneurons in the PFC, expressing calcium-binding proteins, is composed of regular-spiking, calbindin or calretinin-positive cells targeting distal dendrites of pyramidal neurons layers I and IV of the PFC. Calretinin is localized in SST, NPY or VIP-expressing interneurons. VIP interneurons make inhibitory synapses on SST or PV interneurons [7]. SST neurons target distal dendrites of pyramidal cells in layers II, V and VI [2]. The PFC forms the administrative centre where information is processed and integrated to execute complex functions, such as planning, working memory, attention, decision making and goal-directed behaviour. This region also involves emotional processing, including affection, emotion, and social behaviour [2].
There are two vulnerable periods in PFC development, the perinatal period and adolescence, and impairments of these developmental stages result in abnormal cortical development and functional disability [8]. During the perinatal period, several critical processes for cortical growth are observed: neuronal proliferation, neuronal differentiation and synaptogenesis. In adolescence only, synapse pruning, together with increased myelinisation, is fundamental for neurodevelopment to strengthen and optimise salient connections in the adult brain. The PFC is a brain structure that sustains structural and functional development crosswise from adolescence into early adulthood. The above development trajectory corresponds with a transition in behaviour and cognitive function, i.e., gradual stabilisation of emotional reactivity, novelty seeking, cognitive control and decision making [9].
During adolescent neurodevelopment, 30% of synapses formed during childhood are lost [10]. The eliminated synapses are principally excitatory, and inhibitory neurons’ maturation depends on the excitatory neurons’ inputs. The process is necessary for establishing proper E/I balance in the adult cortex, which is essential for the network dynamics underlying cognitive processes. The PFC goes through a decline in grey matter volume, white content enlargement, and modifications in circuity cytoarchitecture (i.e., axon myelinisation), dendritic morphology and synaptic density that shape the brain and establish proper behavioural responses [11].
Dysfunction of the PFC is a dominant aspect of several psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), bipolar disorder, anxiety and schizophrenia.

2. Prefrontal Cortical Pathology in Schizophrenia

Disturbances in cognitive function are crucial symptoms of schizophrenia. Impairments in attention, memory, and executive functions, i.e., the ability to plan, initiate and regulate goal-directed behaviour are present throughout the entire course of the illness. Cognitive dysfunctions are particularly difficult to treat with antipsychotic medicaments [12]. Cognitive functions, especially working memory, are associated with activating prefrontal cortex circuity, especially the dorsolateral prefrontal cortex, where several specific anatomical and neurochemical abnormalities are observed in schizophrenia [13][14].
Anatomical studies showed that the total number of neurons is not altered in schizophrenia; however, neuronal density increases, which reflects a reduction in the neuropil. These observations consisted of findings showing shorter dendritic length and a lower density of dendritic spines on pyramidal neurons, and a lower level of synaptophysin, a marker of axon terminals [15][16][17]. Moreover, a lower density of perineuronal nets (PNNs), extracellular structures stabilising synapses, support synaptic loss or destabilisation in the PFC of schizophrenia subjects [18]. Some findings indicate 60% synapse loss in schizophrenia [10].
The above alterations suggest dysfunction in neurotransmissions, especially excitatory ones. Abnormalities in glutamatergic signalling seem related to dysfunction in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors localised on dendritic spines [19]. Moreover, proton magnetic resonance spectroscopy (MRS) studies from the PFC showed reduced glutamate levels in schizophrenia [20].
Abnormalities in GABA signalling in the PFC of patients with schizophrenia were also reported. MRS studies from PFC showed mixed results with higher, lower or unchanged levels of GABA in subjects with schizophrenia. Disturbances in signalling between PV basket cells and excitatory pyramidal cells in the PFC contribute to altered γ oscillations and working memory in schizophrenia [5][6].
The PFC’s activity of pyramidal cells and interneurons is modulated by inputs from dopamine neurons located in the ventral mesencephalon. Several findings indicate a reduction in dopamine signalling in the PFC in schizophrenia, and a decrease in dopamine innervations was observed [21]. A positron emission tomography study showed an increased density of dopamine D1 receptors in subjects with schizophrenia that correlated with poor working memory that might be a secondary, possibly a neurodevelopmental, deficit in dopamine innervation [22]. Pathological changes in the PFC suggest loss of synapses and neurotransmission impairments (GABAergic, glutamatergic or dopaminergic) in schizophrenia.

3. Genetic Background of Schizophrenia

Schizophrenia aetiology has a strong genetic component. Gene-associated studies showed a possible relationship between some variants in human genes and the risk of schizophrenia. Some studies pointed out some candidate genes related to dopamine signalling, such as catechol O-methyltransferase (COMT) [23], monoamine oxidase (MAO), dopamine transporter (SLC6A3), and dystrobrevin-binding protein 1 (DTNBP1) [24]. COMT, the dopamine-degrading enzyme, is a main regulator of the prefrontal dopamine level. The allelic variants (Val158Met) in the COMT gene code slightly increase the risk of schizophrenia with increasing prefrontal dopamine catabolism and impairing prefrontal cognition [25]. MAO is a mitochondrial enzyme existing in two forms, MAO-A and MAO-B. MAO plays an essential role in dopamine degradation and regulation of dopaminergic neuron activity. The MAO-B rs 1799836 polymorphism (A to G substitution) was suggested to be connected with the aetiology of schizophrenia and negative symptoms development [25]. Dysbindin, a protein encoded by DTNBP1, is located in the synapses. Dysbindin C-A-T haplotype (risk allele of DTNBP1 rs2619539, rs3213207, rs2619538) is associated with increased risk of schizophrenia [26] and affects brain structure reducing grey matter volume [27].
Key loci associated with schizophrenia risk are related to excitatory neurotransmission: the NMDA receptor (subunit 2A; GRIN2A, the estimated odds ratio for highly damaging coding variants ~24.1), AMPA receptor subunit (GRIA3; the estimated odds ratio for highly damaging coding variants ~20.1) as well as various postsynaptic cell adhesion and scaffolding proteins of excitatory synapses like postsynaptic density protein 93 (PSD-93) and synaptic Ras GTPase activating protein (SYNGAP1), which regulate the NMDA receptor-dependent trafficking of AMPA receptors and synaptic potentiation and are required for proper synaptic function [28][29]. Genetic advances show that schizophrenia is also associated with variants linked to genes affecting GABAergic transmission. Schizophrenia-associated loci encoding proteins involved in inhibitory neurotransmission include GABAB receptor components GABBR1 and GABBR2 and loci linked to proteins that mediate GABA receptor turnover such as ankyrin-G (ANK3), which stabilises somatodendritic GABAergic synapses and, in an rs41283526 variant could be protective against schizophrenia. Furin, a protein affecting inhibitory synaptic transmission by altering the transcription of GABAA receptor subunits, has been implicated in schizophrenia GWASs along with chloride channel CLCN3 and vesicular inhibitory amino acid transporter SLC32A1, involved in GABA uptake into synaptic vesicles [28][30][31].
A genome-wide associated study of more than 36,000 schizophrenia patients and 100,000 controls identified 128 independent associations in 108 loci. Noted associations were relevant to dopamine D2 receptors and many genes involved in glutamatergic neurotransmission and synaptic plasticity (glutamate metabotropic receptor 3, GRM3; glutamate ionotropic receptor NMDA type subunit 2A, GRIN2A; serine racemase, SRR; glutamate ionotropic receptor AMPA type subunit 1, GRIA1). In addition, associations at calcium voltage-gated channel subunit α 1C (CACNA1C), calcium voltage-gated channel auxiliary subunit β 2 (CACNB2) and calcium voltage-gated channel subunit α 1 I (CACNA1I), which encode voltage-gated calcium channel subunits, were also reported [32]. Studies of rare genetic variations also showed genes encoding calcium channels, proteins involved in glutamatergic transmission and synaptic plasticity as a schizophrenia risk [33][34][35]. Moreover, risk variants for schizophrenia aggregate in specific biological pathways such as postsynaptic density, postsynaptic membrane, dendritic spine, and axon part [36]. A recent study using single-cell RNA-sequencing showed in the human-specific granular layer of the PFC 6 schizophrenia-related genes associated with synaptic transmission, cell development and differentiation (Met proto-oncogene, receptor tyrosine kinase, MET; Neurogranin, NRGN; parvalbumin, PVALB; retinoic acid receptor β, RARB; thymocyte expressed, positive selection associated 1, TESPA1; and zinc finger matrin-type 4, ZMAT4). Some of these genes (RARB, ZMAT4) were correlated with grey matter volume differences between patients with schizophrenia and healthy control [37]. Thus, the genetic predisposition to schizophrenia might be related to the regulation of synaptic neurotransmission (i.e., dopaminergic, glutaminergic) and synaptic plasticity.

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