In the prefrontal cortex, N-methyl-D-aspartic acid (NMDA) receptors are critical not only for normal prefrontal functions but also for the pathological processes of schizophrenia. Little is known, however, about the developmental properties of NMDA receptors in the functionally diverse subpopulations of interneurons. We investigated the developmental changes of NMDA receptors in rat prefrontal interneurons using patch clamp recording in cortical slices. We found that fast-spiking (FS) interneurons exhibited properties of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA currents distinct from those in regular spiking (RS) and low-threshold spiking (LTS) interneurons, particularly during the adolescent period. In juvenile animals, most (73%) of the FS cells demonstrated both AMPA and NMDA currents. The NMDA currents, however, gradually became undetectable during cortical development, with most (74%) of the FS cells exhibiting no NMDA current in adults. In contrast, AMPA and NMDA currents in RS and LTS interneurons were relatively stable, without significant changes from juveniles to adults. Moreover, even in FS cells with NMDA currents, the NMDA/AMPA ratio dramatically decreased during the adolescent period but returned to juvenile level in adults, compared to the relatively stable ratios in RS and LTS interneurons. These data suggest that FS interneurons in the PFC undergo dramatic changes in glutamatergic receptors during the adolescent period. These properties may make FS cells particularly sensitive and vulnerable to epigenetic stimulation, thus contributing to the onset of many psychiatric disorders, including schizophrenia.

Abnormal influx of Ca2+ is thought to contribute to the neuronal injury associated with a number of brain disorders, and Ca 2+ -permeable AMPA receptors (CP-AMPARs) play a critical role in the pathological process. Despite the apparent vulnerability of fast-spiking (FS) interneurons in neurological disorders, little is known about the CP-AMPARs expressed by functionally identified FS interneurons in the developing prefrontal cortex (PFC). We investigated the development of inwardly rectifying AMPA receptor-mediated currents and their correlation with NMDA receptor-mediated currents in FS interneurons in the rat PFC. We found that 78% of the FS interneurons expressed a low rectification index, presumably Ca 2+ -permeable AMPARs, with only 22% exhibiting AMPARs with a high rectification index, probably Ca 2+ impermeable (CI). FS interneurons with CP-AMPARs exhibited properties distinct from those expressing CI-AMPARs, although both displayed similar morphologies, passive membrane properties and AMPA currents at resting membrane potentials. The AMPA receptors also exhibited dramatic changes during cortical development with significantly more FS interneurons with CP-AMPARs and a clearly decreased rectification index during adolescence. In addition, FS interneurons with CP-AMPARs exhibited few or no NMDA currents, distinct frequency-dependent synaptic facilitation, and protracted maturation in short-term plasticity. These data suggest that CP-AMPARs in FS interneurons may play a critical role in neuronal integration and that their characteristic properties may make these cells particularly vulnerable to disruptive influences in the PFC, thus contributing to the onset of many psychiatric disorders.

N-methyl-D-aspartic acid (NMDA) receptors are critical for both normal brain functions and the pathogenesis of schizophrenia. We investigated the functional changes of glutamatergic receptors in the pyramidal cells and fast-spiking (FS) interneurons in the adolescent rat prefrontal cortex in MK-801 model of schizophrenia. We found that although both pyramidal cells and FS interneurons were affected by in vivo subchronic blockade of NMDA receptors, MK-801 induced distinct changes in αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors in the FS interneurons compared with pyramidal cells. Specifically, the amplitude, but not the frequency, of AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) in FS interneurons was significantly decreased whereas both the frequency and amplitude in pyramidal neurons were increased. In addition, MK-801-induced new presynaptic NMDA receptors were detected in the glutamatergic terminals targeting pyramidal neurons but not FS interneurons. MK-801 also induced distinct alterations in FS interneurons but not in pyramidal neurons, including significantly decreased rectification index and increased calcium permeability. These data suggest a distinct cell-type specific and homeostatic synaptic scaling and redistribution of AMPA and NMDA receptors in response to the subchronic blockade of NMDA receptors and thus provide a direct mechanistic explanation for the NMDA hypofunction hypothesis that have long been proposed for the schizophrenia pathophysiology.

The noradrenergic system of the brain is thought to facilitate neuronal processes that promote behavioral activation, alertness, and attention. It is known that norepinephrine (NE) can be significantly elevated in the prefrontal cortex under normal conditions such as arousal and attention, and following administration of psychostimulants and various other drugs prescribed for psychiatric disorders. However, how NE modulates neuronal activity and synapses in the local prefrontal circuitry remains elusive. In this study, we characterized the actions of NE on individual monosynaptic connections among layer V pyramidal neurons (P) and fast-spiking (FS) GABAergic interneurons in the juvenile (postnatal days 20–23) rat prefrontal local circuitry. We found that NE selectively depresses excitatory synaptic transmission in P-FS connections but has no detectable effect on the excitatory synapses in P-P connections and the inhibitory synapses in FS-P connections. NE apparently exerts distinctly different modulatory actions on identified synapses that target GABAergic interneurons but has no effect on those in the pyramidal neurons in this specific developmental period. These results indicate that, depending on the postsynaptic targets, the effects of NE in prefrontal cortex are synapse-specific, at least in the juvenile animals.

Recent findings in rodents and non-human primates suggest that divergent cognitive processes are carried out by anatomically distinct subregions of the PFC [5][6][7], although the extent to which these processes can be considered functionally homologous in different www.intechopen.comThe Unique Properties of the Prefrontal Cortex and Mental Illness 5 species remains controversial [8]. As part of the limbic system, the PFC is widely connected with many brain structures, particularly those in the Papez circuit. These wide connections make the PFC extremely responsive to stimulation such as emotion, stress, motivation, and learning and memory processes [6, 9-11]. PFC connections in the rat brainThe rat PFC is divided into the prelimbic, infralimbic, anterior cingulate, agranular insular cortices, and orbitofrontal areas [12][13][14]. Each of these subregions of the PFC appears to make individual contributions to emotional and motivational influences on behavior [15]. The PFC has complex functions such as working memory as well as attention, cognition, emotion and executive control [16]. The glutamatergic pyramidal neurons in the anterior cingulate cortex send descending projections to the nucleus accumbens core, the center for reward and emotional processing [13,17,18]. Additional descending projections from the PFC to nucleus accumbens, amygdala and other limbic brain regions appear to exert regulatory control over reward-seeking behavior. Therefore, the PFC is a key component of the limbic system with many inputs and outputs, and its heterogeneous cytoarchitectonic structure implies a complex functional organization.