Molecular influences on working memory circuits in dorsolateral prefrontal cortex

The working memory circuits of the primate dorsolateral prefrontal cortex (dlPFC) are modulated in a unique manner, often opposite to the molecular mechanisms needed for long-term memory consolidation. Working memory, our "mental sketch pad" is an ephemeral process, whereby transient, mental representations form the foundation for abstract thought. The microcircuits that generate mental representations are found in deep layer III of the dlPFC, where pyramidal cells excite each other to keep information "in mind" through NMDA receptor synapses on spines. The catecholaminergic and cholinergic arousal systems have rapid and flexible influences on the strength of these connections, thus allowing coordination between arousal and cognitive states. These modulators can rapidly weaken connectivity, for example, as occurs during uncontrollable stress, via feedforward calcium-cAMP signaling opening potassium (K(+)) channels near synapses on spines. Lower levels of calcium-cAMP-K(+) channel signaling provide negative feedback within recurrent excitatory circuits, and help to gate inputs to shape the contents of working memory. There are also explicit mechanisms to inhibit calcium-cAMP signaling and strengthen connectivity, for example, postsynaptic α2A-adrenoceptors on spines. This work has led to the development of the α2A agonist, guanfacine, for the treatment of a variety of dlPFC disorders. In mental illness, there are a variety of genetic insults to the molecules that normally serve to inhibit calcium-cAMP signaling in spines, thus explaining why so many genetic insults can lead to the same phenotype of impaired dlPFC cognitive function. Thus, the molecular mechanisms that provide mental flexibility may also confer vulnerability when dysregulated in cognitive disorders.