# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 1 Introduction  
Schizophrenia is a mental disease that affects circa 1% of the general population [1]. Schizophrenia seriously impairs several aspects of everyday life, such as interpersonal relationships or professional activity, often limiting a patient's independence [2]. This mental disease has a chronic character and is characterized by multidimensional symptomatology in the form of productive, negative, affective, and disorganization symptoms, and cognitive deficits.  
Cognitive deficits in schizophrenia are frequent and persistent, prevalent in 60-70% of patients [3]. Persistent disability in schizophrenia results mainly from cognitive disturbances and negative symptoms [4; 5; 6]. Chronic persistence of cognitive disturbances in schizophrenia is the worst prognostic factor for a patient's social abilities [7]. In turn, an improvement of cognitive functioning is related to better social functioning [8].  
Many long-term studies indicate the cognitive dysfunctions in schizophrenia are present at an early stage of the disease, even before the acute phase develops, and then they become chronic withno complete improvement in the coming years [9; 10; 11; 12; 13; 14; 15]. Cognitive deficits start in most patients before the first schizophrenic episode and are not present in childhood [16]. For this reason, cognitive disturbances are understood to be the primary symptoms of schizophrenia [17].  
Cognitive deficits are linked with so-called hypofrontality. Hypofrontality is the reduced utilization of glucose and decreased blood flow in the prefrontal cortex, that implies the decrease of neuronal metabolism and impaired cognition [18]. The concept of hypofrontality is broadly described in the literature of schizophrenia, although the phenomenon is not fully understood and the strict neuronal mechanism of it is not known. It is supposed that hypofrontality relates to impairment of neuronal transmission and synaptic connectivity, that are based on genetic predisposition and neurodevelopmental disturbances [18].  
Identification of mechanisms of how cognitive impairment develops in schizophrenia and finding its effective treatment is crucial for the improvement of health and functioning of patients with schizophrenia. On a theoretical basis, the glutamatergic N-methyl-D-aspartic acid receptors (NMDARs) play an important role in the mechanism of development and maintenance of cognitive deficits in schizophrenia. It is known that cognitive deficits in schizophrenia relate to disturbances of transmission in the corticolimbothalamic circuit [18]. The transmission in that loop is regulated by NMDARs on GABA-ergic inhibitory interneurons. Besides that, NMDARs in synapses play their essential role in neuronal connectivity.  
We designed a series of experimental studies to evaluate the expression of NMDAR subunits in structures belonging to the corticolimbothalamic circuit. They aimed to elucidate how antipsychotic drugs, used in the treatment of schizophrenia, modulate the NMDAR composition, and indirectly, how they influence the receptor activity and the activity of the glutamatergic system.