Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

M1 receptors interacting with NMDAR enhance delay-related neuronal firing and improve working memory performance.

The recurrent excitatory circuits in dlPFC underlying working memory are known to require activation of glutamatergic NMDA receptors (NMDAR). The neurons in these circuits also rely on acetylcholine to maintain persistent activity, with evidence for actions at both nicotinic α7 receptors and muscarinic M1 receptors (M1R). It is known that nicotinic α7 receptors interact with NMDAR in these circuits, but the interactions between M1R and NMDAR on dlPFC neuronal activity are unknown. Here, we investigated whether M1Rs contribute to the permissive effects of ACh in dlPFC circuitry underlying working memory via interactions with NMDA receptors. We tested interactions between M1Rs and NMDARs in vivo on single neuron activity in rhesus macaques performing a working memory task, as well as on working memory behavior in rodents following infusion of M1R and NMDAR compounds into mPFC. We report that M1R antagonists block the enhancing effects of NMDA application, consistent with M1R permissive actions. Conversely, M1R positive allosteric modulators prevented the detrimental effects of NMDAR blockade in single neurons in dlPFC and on working memory performance in rodents. These data support an interaction between M1R and NMDARs in working memory circuitry in both primates and rats, and suggest M1Rs contribute to the permissive actions of ACh in primate dlPFC. These results are consistent with recent data suggesting that M1R agonists may be helpful in the treatment of schizophrenia, a cognitive disorder associated with NMDAR dysfunction.

Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer's disease: A tracer kinetic modeling study.

[11C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer's disease (AD). We compared [11C]UCB-J binding for synaptic density and [18F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11C]UCB-J binding to SV2A; and Ki or KiR to cerebellum for [18F]FDG metabolism. [11C]UCB-J binding and [18F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD -compared to CN participants. However, the magnitude of reduction of [11C]UCB-J binding in neocortical regions was less than that observed with [18F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11C]UCB-J perfusion showed a similar pattern to [18F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.

Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder.

BACKGROUND: Methylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear. Recent studies have identified an oral, MPH dose regimen which when given to rats produces drug plasma levels similar to those measured in humans. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC), a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. The receptor mechanisms underlying the enhancing effects of MPH were explored by challenging the MPH response with the noradrenergic alpha2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390. RESULTS: MPH produced an inverted U dose response whereby moderate doses (1.0-2.0 mg/kg, p.o.) significantly improved delayed alternation performance, while higher doses (2.0-3.0 mg/kg, p.o.) produced perseverative errors in many animals. The enhancing effects of MPH were blocked by co-administration of either the alpha2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own. CONCLUSION: The administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic alpha2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.