Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders

Abstract

Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from "long-COVID" or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC) that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are especially vulnerable to kynurenic acid inflammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual neuromodulation, with cAMP magnification of calcium signaling in spines, which opens nearby potassium channels to rapidly weaken connectivity and reduce neuronal firing. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to prevent loss of firing. However, the production of GCPII inflammatory signaling reduces mGluR3 actions and markedly diminishes dlPFC network firing. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network firing and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the locus coeruleus and amygdala, and by having anti-inflammatory actions in the immune system. This information is particularly timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the treatment of cognitive deficits from long-COVID.

Fig. 1. Schematic illustration of neurotransmission and neuromodulation in a classic vs. dlPFC glutamate synapse.

A In a classic glutamate synapse, neurotransmission depends on AMPA receptors, which depolarize the postsynaptic membrane to eject Mg²⁺ from the NMDAR pore and allow NMDAR neurotransmission (i.e.”permissive” actions). The calcium entry through NMDAR can drive cAMP-PKA signaling to increase neuroplasticity and strengthen connections. cAMP is catabolized by PDE4s, which reduce memory formation. In traditional glutamate synapses, mGluR3 are often presynaptic, where they reduce glutamate release. B In contrast to traditional glutamate circuits which depend heavily on AMPAR, layer III dlPFC circuits have little AMPAR dependence, and instead rely most heavily on NMDAR and nic-α7R, which reside within the glutamate synapse and help to depolarize the postsynaptic membrane, needed to eject the Mg²⁺ for NMDAR actions. Depolarization may also be supported by high levels of calcium, including cAMP-PKA magnification of calcium release from the smooth endoplasmic reticulum (SER), shown in pink. Calcium in turn drives cAMP production, leading to feedforward signaling. Higher levels of cAMP-PKA-calcium signaling open K⁺ channels to weaken connectivity and have dynamic changes in synaptic strength, reducing firing under conditions of high cAMP-calcium signaling (see Fig. 2). Under healthy conditions, feedforward cAMP-PKA-calcium-K⁺ signaling is tightly regulated, by postsynaptic mGluR3 and α2A-AR inhibition of cAMP synthesis, by PDE4 catabolism of cAMP, and calbindin binding of cytosolic calcium.

Fig. 2. The unusual molecular properties of primate layer III dlPFC make it particularly vulnerable to neuroinflammation, including loss of neuronal firing, loss of synapses, and tau phosphorylation.

Kynurenine is made and released under inflammatory conditions and metabolized to KYNA in brain, where it blocks NMDAR and nic-α7R, which would greatly reduce dlPFC neurotransmission. Reactive microglia and astroctyes make and release GCPII, which catabolizes NAAG and thus reduces mGluR3 regulation of cAMP synthesis. There also can be loss of PDE4s and calbindin (not shown, see text). Psychological and physiological stress release high levels of catecholamines in PFC, that drive cAMP-PKA-calcium signaling; anesthesia can also increase calcium release from the SER. Dysregulated cAMP-PKA-calcium signaling leads to: 1) loss of neuronal firing via opening of K⁺ channels, 2) calcium overload of mitochondria, initiating inflammatory signaling including signals to microglia to remove synapses, and 3) tau hyperphosphorylation, e.g. through calpain 2 cleavage and activation of GSK3β and cdk5, the primary kinases that phosphorylate tau.

Fig. 3. NE acts as a neurochemical switch, determining whether recently evolved or primitive brain circuits govern behavior.

A Under nonstressful, healthy conditions, moderate levels of NE release engage high affinity α2A-ARs, strengthening the PFC and weakening the amygdala. Thus, there is strong top-down control of attention, action and emotion. B Under conditions of physiological or psychological stress, high levels of NE release activate low affinity α1-AR and β-AR, which weaken the PFC and strengthen the amygdala, switching the brain into a more primitive state. Treatment with the α2A-AR agonist, guanfacine, can transition the brain back into a regulated state.

Fig. 4. The α2A-AR agonist, guanfacine, restores synaptic connectivity in PFC through both direct and indirect actions.

Guanfacine directly strengthens dlPFC connections and neuronal firing by inhibiting cAMP-PKA-calcium-K⁺ signaling in layer III spines. It can also have indirect benefits through its anti-inflammatory actions.

Fig. 5. Widespread α2-adrenoceptor actions.

α2-adrenoceptor agonists have multiple actions throughout the nervous and immune systems in ways that may benefit the treatment of neuroinflammatory cognitive disorders.