Why build a vacation home for a one-week holiday when you can rent out a hotel room? Short-term stays do not require the construction of permanent structures. Similarly, working memory does not require the changes in synaptic structures involved in short- and long-term memory. Instead, working memory involves the recurrent firing of neural circuits in the prefrontal cortex. What are the molecular mechanisms involved in modulating these circuits? Wang et al. report that a2A-adrenoceptors stimulate working memory by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in dendritic spines in a recent article in Cell.
The catecholamines epinephrine and norepinephrine act at α2A-adrenoceptors to decrease cyclic AMP (cAMP). Moderate levels of norepinephrine increase attention. The α2A-adrenoceptor agonist guanfacine is prescribed to treat disorders that affect concentration, including attention deficit hyperactivity disorder (ADHD), Tourette syndrome and mild traumatic brain injury.
In a working memory task, α2A-adrenoceptors regulate the activity of prefrontal cortex neurons. The oculomotor spatial delayed response task tests a monkey's ability to remember the location of an illuminated spot on a circle after a delay of several seconds. Each neuron in the monkey prefrontal cortex is 'tuned' to a specific direction on the circle: when a neuron's preferred direction is illuminated, it fires trains of action potentials. The authors recorded from prefrontal cortex neurons treated locally with drugs in monkeys performing this task. Relative to vehicle treatment, guanfacine increased and the α2A-adrenoceptor antagonist yohimbine reduced the firing of weakly tuned neurons to their preferred direction, suggesting that α2A-adrenoceptor activity regulates the spatial tuning of prefrontal cortex neurons.
The phosphodiesterase inhibitor etazolate blocks the breakdown of cAMP. Etazolate decreased but the cAMP inhibitor Rp-cAMPS increased the spatially tuned firing of neurons to their preferred directions. The cAMP analog Sp-cAMPS blocked the guanfacine-induced increase in spatial tuning, suggesting that α2A-adrenoceptor activation enhances the activity of prefrontal cortex neurons by reducing cAMP.
HCN channels are activated by cAMP. The HCN channel blocker ZD7288 increased the firing of weakly tuned prefrontal cortex neurons to their preferred directions and reversed the stimulatory effect of guanfacine, suggesting that α2A-adrenoceptor activation strengthens the spatially tuned activity of prefrontal cortex neurons by blocking HCN channels.
Blocking HCN channels improves performance in working memory tasks. Rats reintroduced to a T-maze several seconds after exploring one arm remember their previous location and explore the opposite arm. Rats with HCN expression reduced by short interfering RNA or treated with ZD7288 showed improved performance in this delayed alternation task relative to control rats. However, rats treated with both ZD7288 and Sp-cAMPS alternated arms like vehicle-treated rats, indicating that cAMP activation rescued HCN inhibition.
HCN1 channels colocalized with α2A-adrenoceptors in dendritic spines in monkey prefrontal cortex neurons, suggesting that norepinephrine acts at α2A-adrenoceptors on dendritic spines to reduce levels of cAMP, blocking local HCN channels. Open HCN channels pass current out of the cell, so closing HCN channels may strengthen neuron firing by blocking current leaks.
According to the authors, working memory disruptions caused by diseases, such as schizophrenia, may be due to dysregulation of cAMP.