Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

Abstract

Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC) and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought. Importantly, excitatory synapses on layer III spines are uniquely regulated at the molecular level in ways that may render them particularly vulnerable to genetic and/or environmental insults. Glutamate actions are remarkably dependent on cholinergic stimulation, and there are inherent mechanisms to rapidly weaken connectivity, e.g. during stress. In particular, feedforward cyclic adenosine monophosphate (cAMP)-calcium signaling rapidly weakens network connectivity and neuronal firing by opening nearby potassium channels. Many mechanisms that regulate this process are altered in schizophrenia and/or associated with genetic insults. Current data suggest that there are “dual hits” to layer III dlPFC circuits: initial insults to connectivity during the perinatal period due to genetic errors and/or inflammatory insults that predispose the cortex to atrophy, followed by a second wave of cortical loss during adolescence, e.g. driven by stress, at the descent into illness. The unique molecular regulation of layer III circuits may provide a nexus where inflammation disinhibits the neuronal response to stress. Understanding these mechanisms may help to illuminate dlPFC susceptibility in schizophrenia and provide insights for novel therapeutic targets.

Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex

“…In contrast, PE is nonselective between subtypes (Minneman et al, 1994). It is possible that ␣1-AR excitatory effects in primate dlPFC involve ␣1d-AR actions, for example, increasing presynaptic glutamate release, whereas the suppressive effects involve ␣1a-AR actions, for example, at postsynaptic receptors that engage calcium-PKC-K ϩ signaling (Datta and Arnsten, 2018). The latter idea is supported by in vitro data showing that the ␣1a-AR subtype engages PKC signaling more potently than ␣1d-ARs (Taguchi et al, 1998).…”

“…These cellular data explain why both PE infusion directly into monkey dlPFC (Mao et al, 1999) or systemic administration of cirazoline (Arnsten and Jentsch, 1997) impairs working memory performance in monkeys. Previous research indicates that these impairing actions involve calcium-PKC signaling (Birnbaum et al, 2004), which can drive feedforward calcium-PKC-cAMP signaling and reduce firing through opening of K ϩ channels in layer III dlPFC spines (Datta and Arnsten, 2018) (Fig. 9B).…”

“…A similar pattern was seen in monkey, with axonal labeling in both nonterminal and terminal regions and the spine labeling occasionally within the PSD, but mostly distant from the synapse often near the calcium-containing spine apparatus. ␣1-AR in the PSD may phosphorylate NMDARs to maintain receptors in the synapse and promote excitatory actions, as suggested by physiological recordings in rat mPFC (Luo et al, 2014), whereas ␣1-ARs more distant from the PSD may engage calcium-cAMP-K ϩ channel actions that reduce firing (Datta and Arnsten, 2018).…”

Persistence: Using Protein Turnover to Expand the Applications of Transcriptomics

“…Multiple studies in animals, iPSCs, and humans have noted increased potassium and sodium channel expression and activity in the prefrontal cortex. These changes were associated with abnormal neuronal activity, diminished synaptic plasticity, and impaired white matter integrity, all of which are characteristic of SCZ [17][18][19][20][21][22]. Additionally, antipsychotics can reverse these ion channel alterations, suggesting that this is a key mechanism in SCZ pathology [23][24][25].…”

“…These results are encouraging that persistence is a meaningful measure because these pathways have been implicated in SCZ in prior studies. For example, ion homeostasis was the most commonly altered category in our high persistent pathways [17][18][19][20][21][22].…”