Neocortical network activity is generated through a dynamic balance between excitation, provided by pyramidal neurons, and inhibition, provided by interneurons. Imbalance of the excitation/inhibition ratio has been identified in several neuropsychiatric diseases, such as schizophrenia, autism and epilepsy, which also present with other cognitive deficits and symptoms associated with prefrontal cortical (PFC) dysfunction. We undertook a computational approach to study how changes in the excitation/inhibition balance in a PFC microcircuit model affect the properties of persistent activity, considered the cellular correlate of working memory function in PFC. To this end, we constructed a PFC microcircuit, consisting of pyramidal neuron models and all three different interneuron types: fast-spiking (FS), regular-spiking (RS), and irregular-spiking (IS) interneurons. Persistent activity was induced in the microcircuit model with a stimulus to the proximal apical dendrites of the pyramidal neuron models, and its properties were analyzed, such as the induction profile, the interspike intervals (ISIs) and neuronal synchronicity. Our simulations showed that (a) the induction but not the firing frequency or neuronal synchronicity is modulated by changes in the NMDA-to-AMPA ratio on FS interneuron model, (b) removing or decreasing the FS model input to the pyramidal neuron models greatly limited the biophysical modulation of persistent activity induction, decreased the ISIs and neuronal synchronicity during persistent activity, (c) the induction and firing properties could not be altered by the addition of other inhibitory inputs to the soma (from RS or IS models), and (d) the synchronicity change could be reversed by the addition of other inhibitory inputs to the soma, but beyond the levels of the control network. Thus, generic somatic inhibition acts as a pacemaker of persistent activity and FS specific inhibition modulates the output of the pacemaker.

Adolescence is a highly vulnerable period for the emergence of major neuropsychological disorders and is characterized by decreased cognitive control and increased risk-taking behavior and novelty-seeking. The prefrontal cortex (PFC) is involved in the cognitive control of impulsive and risky behavior. Although the PFC is known to reach maturation later than other cortical areas, little information is available regarding the functional changes from adolescence to adulthood in PFC, particularly compared with other primary cortical areas. This study aims to understand the development of PFC-mediated, compared with non-PFC-mediated, cognitive functions. Toward this aim, we performed cognitive behavioral tasks in adolescent and adult mice and subsequently investigated synaptic plasticity in two different cortical areas. Our results showed that adolescent mice exhibit impaired performance in PFC-dependent cognitive tasks compared with adult mice, whereas their performance in non-PFC-dependent tasks is similar to that of adults. Furthermore, adolescent mice exhibited decreased long-term potentiation (LTP) within upper-layer synapses of the PFC but not the barrel cortex. Blocking GABA receptor function significantly augments LTP in both the adolescent and adult PFC. No change in intrinsic excitability of PFC pyramidal neurons was observed between adolescent and adult mice. Finally, increased expression of the NR2A subunit of the N-methyl-d-aspartate receptors is found only in the adult PFC, a change that could underlie the emergence of LTP. In conclusion, our results demonstrate physiological and behavioral changes during adolescence that are specific to the PFC and could underlie the reduced cognitive control in adolescents. NEW & NOTEWORTHY This study reports that adolescent mice exhibit impaired performance in cognitive functions dependent on the prefrontal cortex but not in cognitive functions dependent on other cortical regions. The current results propose reduced synaptic plasticity in the upper layers of the prefrontal cortex as a cellular correlate of this weakened cognitive function. This decreased synaptic plasticity is due to reduced N-methyl-d-aspartate receptor expression but not due to dampened intrinsic excitability or enhanced GABAergic signaling during adolescence.

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GABAergic (γ-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities in oscillatory activity, especially in the gamma frequency range (30–80 Hz). We investigated the functional changes in cortical network activity in response to developmentally reduced inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays ∼50% fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells [Rac1 conditional knockout (cKO) mice], to examine how this developmental loss of cortical interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity, and neuronal oscillations in the adult BC. The decrease in the number of interneurons increased basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio (PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit enhanced sensitivity and susceptibility to emergent spontaneous activity. We also find that this developmental decrease in the number of cortical interneurons results in local neuronal networks with alterations in neuronal oscillations, exhibiting decreased power in low frequencies (delta, theta, alpha) and gamma frequency range (30–80 Hz) with an extra aberrant peak in high gamma frequency range (80–150 Hz). Therefore, our data show that disruption in GABAergic inhibition alters synaptic properties and plasticity, while it additionally disrupts the cortical neuronal synchronization in the adult BC.