Postnatal Developmental Trajectories of Neural Circuits in the Primate Prefrontal Cortex: Identifying Sensitive Periods for Vulnerability to Schizophrenia

Abstract

Schizophrenia is a disorder of cognitive neurodevelopment with characteristic abnormalities in working memory attributed, at least in part, to alterations in the circuitry of the dorsolateral prefrontal cortex. Various environmental exposures from conception through adolescence increase risk for the illness, possibly by altering the developmental trajectories of prefrontal cortical circuits. Macaque monkeys provide an excellent model system for studying the maturation of prefrontal cortical circuits. Here, we review the development of glutamatergic and γ-aminobutyric acid (GABA)-ergic circuits in macaque monkey prefrontal cortex and discuss how these trajectories may help to identify sensitive periods during which environmental exposures, such as those associated with increased risk for schizophrenia, might lead to the types of abnormalities in prefrontal cortical function present in schizophrenia.

Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty

“…Male monkeys enter puberty at ∼3.5 y of age and reach full sexual maturity at 5 y, approximately equivalent to the human ages of 11 y and 16 y, respectively (25,26). By some accounts, biochemical and anatomical changes characteristic of adolescence in humans occur at an earlier, prepubertal age in the monkey prefrontal cortex (27,28), so it is not known if cognitive maturation or neurophysiological changes occur in monkeys after puberty. The contribution of prefrontal cortex to antisaccade performance has also been a matter of debate, with contrasting views favoring mechanisms of inhibiting movement toward the visual stimulus or enhancing movement away from it (29)(30)(31).…”

The Unique Properties of the Prefrontal Cortex and Mental Illness

“…In the past two decades, numerous studies have been focused on detail changes in the functional maturation of the PFC circuitry. For example, it is now clear that the underlying synaptic refinement process in the PFC is not completed until late adolescence and early adulthood [110,111], which coincides with the period when symptoms of schizophrenia typically begin to emerge [112]. Indeed, our study indicated that the NMDA receptor subunit NR2B-to-NR2A shift does not occur during prefrontal development.…”

“…Importantly, D2 agonists were effective only in adult but not in prepubertal animals [115]. Many other late occurring changes in GABAergic neurons, GABAergic neurotransmission and GABA A receptors have also been demonstrated [112,116,117]. Similarly, developmental trends have been reported for the dopaminergic [118] and glutamatergic systems [119] and for interactions of these neurotransmitters with GABAergic interneurons.…”

“…As discussed above, PFC cognitive functions rely on networks of interconnected pyramidal cells [1,2,69], as well as GABAergic interneurons [112,116,140]. Recent studies reveals that neuronal connections in the PFC network are influenced by powerful molecular events that determine whether a network is connected or disconnected at a given moment, thus determining the strength of cognitive abilities [70].…”

“…A remarkable number of genetic insults in schizophrenia involve proteins found at prefrontal synapses. There are well-established genetic changes associated with NMDA receptor signaling [160][161][162], DA [51,[163][164][165], GABA [112,116,140,166], and α7 nicotinic receptors [167][168][169][170]. More recently, a number of high-risk genes are found to be associated with schizophrenia [171].…”