Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories

Abstract

Individuals with schizophrenia (SZ) exhibit cognitive performance below expected levels based on familial cognitive aptitude. One such cognitive process, working memory (WM), is robustly impaired in SZ. These WM impairments, which emerge over development during the premorbid and prodromal stages of SZ, appear to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex. Within the dorsolateral prefrontal cortex, a microcircuit formed by reciprocal connections between excitatory layer 3 pyramidal neurons and inhibitory parvalbumin basket cells (PVBCs) appears to be a key neural substrate for WM. Postmortem human studies indicate that both layer 3 pyramidal neurons and PVBCs are altered in SZ, suggesting that levels of excitation and inhibition are lower in the microcircuit. Studies in monkeys indicate that features of both cell types exhibit distinctive postnatal developmental trajectories. Together, the results of these studies suggest a model in which 1) genetic and/or early environmental insults to excitatory signaling in layer 3 pyramidal neurons give rise to cognitive impairments during the prodromal phase of SZ and evoke compensatory changes in inhibition that alter the developmental trajectories of PVBCs, and 2) synaptic pruning during adolescence further lowers excitatory activity to a level that exceeds the compensatory capacity of PVBC inhibition, leading to a failure of the normal maturational improvements in WM during the prodromal and early clinical stages of SZ. Findings that support as well as challenge this model are discussed.

Keywords: Cognition; GABA; Gamma oscillations; Glutamate; Schizophrenia; Working memory.

Figure 1.

Schematic summary of the DLPFC layer 3 pyramidal neuron (PN) – PV basket cell (PVBC) circuit across monkey development (left panel) and in schizophrenia (SZ) (right panel). During postnatal development in monkeys, the density of dendritic spines on the basilar dendrites of layer 3 PNs (orange) increases during the immediate postnatal period and through the prepubertal period; spine density then reaches a plateau until synaptic pruning is initiated during the peripubertal period(66). In PVBCs (blue), levels of PV protein in the cell bodies(113) and axon terminals(109, 110) increase (depicted here as increasing color saturation), with adult levels of the protein achieved in the postpubertal period. Expression levels of the GABA_A α1 receptor subunit (blue ovals), which is enriched at PVBC inputs, increase in layer 3 PNs between the pre- and postpubertal periods(149), coincident with the maturation of PVBC inputs. Levels of proteins that index the strength of excitatory inputs (orange triangles) onto PVBCs increase between the pre- and postpubertal periods, whereas the density of these inputs declines between the prepubertal and peripubertal periods(113), coinciding with the pruning of spines on layer 3 PNs. In our proposed model of SZ, alterations in components of this circuitry are present at every developmental stage. First, the density of dendritic spines is predicted to be lower early in postnatal development due to impaired spinogenesis, with this deficit becoming greater during adolescence due to elevated spine pruning. Second, the lower PV levels in PVBC boutons present in adult individuals with SZ are predicted to be a consequence of PV levels not increasing during the peripubertal period(98, 99). Third, as part of the compensatory response to deficient excitatory drive from fewer spines, layer 3 PNs do not exhibit the peripubertal increase in GABA_A α1 receptor subunit mRNA levels(143) (Note: these findings have not been demonstrated at the protein level as depicted here). Finally, although the protein levels of pre- and postsynaptic indices of excitatory inputs onto PVBCs are not altered at any developmental stage in SZ, the density of excitatory inputs is predicted to decline across the peripubertal and postpubertal periods(97), coincident with the predicted excessive excitatory synapse pruning onto layer 3 PNs across these periods. In this model, the insufficient formation and subsequent excessive pruning of dendritic spines in SZ results in a progressive reduction in excitatory drive to layer 3 PNs. This reduction in activity evokes compensatory downregulation of inhibition from PVBCs, but later developmental declines in excitation exceeds the capacity of the inhibitory system to compensate further. Together, these alterations are manifest as lower levels of excitation and inhibition which are insufficient to maintain the neural activity necessary for proper WM function during the prodromal and early clinical stages of SZ.