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The prefrontal cortex (PFC) has attracted great research interest because of its involvement in the control of executive functions in both health and disease, and particularly in cognitive functions such as working memory. In schizophrenia, alterations in the PFC are documented at many different levels: molecular, cellular and functional. Furthermore, deficits in cognitive abilities are considered a core feature of schizophrenia and remain a major unmet medical need with respect to this disorder. In order to understand the sites of action of currently-used drugs, as well as of the new experimental treatments being developed and acting in this brain region, it is important to have detailed knowledge of the corresponding chemical Fallon et al. 2003). The PFC is described as a six-layered structure, as other neocortical regions, and it is distinguished by a granular layer IV (see Figure 1).In primates the PFC orchestrates thoughts and actions, as well as the planning of complex cognitive and affective functions, and it is therefore implicated in mood disorders (Ebert and Ebmeier 1996). The orbital and medial regions are involved in the control of emotional behavior, whereas the lateral regions, which are highly developed in humans, provide cognitive support to the temporal organization of behavior, speech, reasoning and the execution of complex behaviors that require working memory, as already mentioned; for reviews see (Cavada et al. 2000;Elston 2003;Fuster 1997; Goldman-Rakic et al. 1984).The PFC receives projections from the amygdala (Barbas and de Olmos 1990), the ventral striatum (Kunishio and Haber 1994) and thalamus (Barbas et al. 1991).Specifically, it receives dopaminergic efferents from the ventral tegmental area (VTA) (Berger et al. 1988; Conde et al. 1995;Lindvall et al. 1978) and serotonergic innervation from the median and dorsal raphe nuclei (Berger et al. 1988;Smiley and Goldman-Rakic 1996b), while it sends glutamatergic projections to both the VTA and the nucleus accumbens (Sesack and Pickel 1992;Taber et al. 1995), as well as to the raphe nuclei (Sesack et al. 1989). The PFC is connected with other association cortices but not with primary sensory or motor cortices. There is an important internal network of connectivity between the different divisions of the PFC; indeed, each of the three major prefrontal regions (orbital, medial and lateral) is connected with itself and with the other two. Some of the cortico-cortical connectivity of the PFC is interhemispheric and the majority is organized in a reciprocal and topographical 4 manner (Cavada and Goldman-Rakic 1989a; 1989b). These cortico-cortical connections originate and terminate in upper cortical layers II and III (Andersen et al. 1985).As in other cortical regions, there are two main cell types in the PFC. One is the pyramidal and spiny stellate cells characterized by the excitatory asymmetric synapses which they form (glutamatergic). The majority of cortical neurons are pyramidal output neurons, found mainly in layers II-VI. The othe...

Serotonin 1A (5-HT 1A ) receptors are found in high densities in prefrontal cortex. However, their distribution within cortical cell populations is unknown in both humans and primates. We used double in situ hybridization histochemistry to quantify the percentage of glutamatergic and GABAergic neurons expressing 5-HT 1A receptors in human and monkey prefrontal cortex. Moreover, in the case of the monkey, we also quantified the parvalbumin and calbindin GABAergic subpopulations expressing this receptor. 5-HT 1A receptor mRNAs were expressed in about 80% of glutamatergic neurons in external layers II and upper III, and in around 50% in layer VI; they were also present in approximately 20% of GABAergic neurons in both species. Although they were found in up to 43% of the calbindin cell subpopulation they were rarely present in parvalbumin cells in monkey prefrontal cortex. The knowledge of the phenotype of the prefrontal cortex (PFC) cells expressing 5-HT 1A will help understanding serotonin actions in PFC.

D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15-20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons.

The marked anatomical and functional changes taking place in the medial prefrontal cortex (PFC) during adolescence set grounds for the high incidence of neuropsychiatric disorders with adolescent onset. Although circuit refinement through synapse pruning may constitute the anatomical basis for the cognitive differences reported between adolescents and adults, a physiological correlate of circuit refinement at the level of neuronal ensembles has not been demonstrated. We have recorded neuronal activity together with local field potentials in the medial PFC of juvenile and adult mice under anesthesia, which allowed studying local functional connectivity without behavioral or sensorial interference. Entrainment of pyramidal neurons and interneurons to gamma oscillations, but not to theta or beta oscillations, was reduced after adolescence. Interneurons were synchronized to gamma oscillations across a wider area of the PFC than pyramidal neurons, and the span of interneuron synchronization was shorter in adults than juvenile mice. Thus, transition from childhood to adulthood is characterized by reduction of the strength and span of neuronal synchronization specific to gamma oscillations in the mPFC. The more restricted and weak ongoing synchronization in adults may allow a more dynamic rearrangement of neuronal ensembles during behavior and promote parallel processing of information.

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