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Working Memory—Adrenoreceptors and DISC1 in the Same cAMP?

1 May 2007. In the April 20 issue of Cell, Amy Arnsten and colleagues at Yale University, New Haven, Connecticut, report that adrenergic stimulation enhances working memory by blocking cyclic AMP (cAMP) in the dendritic spines of neurons in prefrontal cortex (PFC). With cAMP held at bay, the results suggest, cAMP gated ion channels remain closed, prolonging the synaptic effects of glutamatergic transmission within the postsynaptic membrane and maintaining the temporary networks required for working memory circuits.

The results may give some traction to research into drugs that improve working memory, which has been found to be compromised in people with schizophrenia. The paper may also provide a link to one of the "hot" schizophrenia gene candidates. Because disrupted in schizophrenia 1 (DISC1) has been reported to limit cAMP signaling by releasing active phosphodiesterase (see Millar et al., 2005), the principal means of destroying cAMP, Arnsten and colleagues suggest that DISC1 mutations might hamper working memory by allowing cAMP levels to remain elevated.

Adrenoreceptors and Working Memory
Working memory, or scratch-pad memory as it is often called, is a short-term, quickly rewritten memory storage system that plays a crucial role in everyday behavior and decision making. In humans, working memory greatly depends on the prefrontal cortex, an area of the brain that is highly evolved in primates. “What we have found is a mechanism involving cAMP that very powerfully controls whether cortical networks in the PFC are connected or disconnected functionally,” said Arnsten. Impaired working memory has been identified as an important cognitive deficit in the disease, and the prefrontal cortex, particularly the dorsolateral PFC, has been identified as a major site of perturbed activity in patients with schizophrenia.

Arnsten and colleagues set out to explore the role of adrenoreceptors in working memory. Previous work showed that stimulation of the postsynaptic α2A adrenoreceptor (AR) plays a critical role in the process and that α2A-AR agonists enhance working memory in animal models. Since α2A agonists (guanfacine and clonidine) are safely used to treat hypertension (with off-label use for many other disorders), there have been opportunities to test the drugs for cognitive enhancement. The benefits for working memory or other cognitive tasks have been deemed promising, but not unequivocally positive, whether in normal controls (see, e.g., Müller et al., 2005) or schizophrenia (Friedman et al., 2001). A recent report found that guanfacine improved working memory in schizotypal personality disorder (McClure et al., 2006), but given the sedation that is a common side effect of α2A agonists, it may be more important to follow the adrenergic lead to other potential molecular targets.

How α2A-AR activation enhances working memory has not been fully worked out. While there are indications that suppression of cAMP is involved, it is unclear how this translates into improved working memory, especially as it would directly contrast with what is known about another form of memory—long-term memory—which requires cAMP-dependent gene activation.

To address these issues, first author Min Wang and colleagues turned to an in-vivo model of spatial working memory—a primate occulomotor spatial delayed response (ODR) task. In this model, neurons in the PFC can be individually recorded as monkeys remember the location of a spot that briefly appears on a TV screen. Neurons that are involved in remembering the location of the spot continue to fire after the spot disappears. This delay-related neuronal activity is a well-accepted model of spatial working memory, and depends on a network of interconnected PFC cells that excite each other to keep the information "in mind" during the delay period.

Wang and colleagues found that administration of the α2A-AR agonist guanfacine strengthened delay-related firing of PFC neurons, while a metabolically stable cAMP analog, Sp-cAMPS, not only weakened PFC firing, but reversed the effect of guanfacine. The findings support the idea that adrenergic stimulation supports working memory by attenuating cAMP. But how does lowering cAMP lead to better working memory? Wang and colleagues hypothesized that the cyclic nucleotide may attenuate PFC firing by opening a gated cation channel called the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. “Activating HCN channels is like punching a big hole in the membrane because they allow both sodium and potassium to flow through, and since they greatly reduce membrane resistance when they are open, the effects at any synapse nearby are greatly reduced,” said Arnsten.

To investigate this idea, Wang and colleagues tested PFC neurons in the presence of the HCN channel blocker ZD7288. The blocker significantly increased delay-related firing in PFC neurons during the ODR task, suggesting that activating these channels might be the mechanism whereby cAMP dampens working memory. To see if HCN channel activation may be related to adrenergic effects, the researchers probed if ZD7288 can overcome the effects of inhibiting α2A-ARs with the antagonist yohimbine. While yohimbine alone suppressed delay-related firing of PFC neurons, the HCN blocker relieved this suppression. “These data support a functional interaction between α2A-ARs and HCN channels at the physiological level,” write the authors.

Short Circuiting PFC Synapses
The researchers extended these observations to other models of PFC circuitry. They found that, in tissue slices, reduction of HCN activity enhances network interactions, while reducing HCN activity in rats (by infusing low doses of ZD7288) improved animal performance in a T-maze model of spatial working memory. All told, the experiments suggest a model whereby cAMP disconnects neural networks in the PFC by opening HCN channels and shunting synaptic inputs out of the dendritic spine (schematically depicted in diagram below).

A Potential Role for DISC1 in Regulating Working Memory Networks
By this model, DISC1 normally reduces cAMP levels by enhancing the activity of phosphodiesterase 4 (PDE4), thereby facilitating the connection of PFC networks (left). Mutations that cause loss of function of DISC1 may lead to inadequate PDE4 activity, excessive cAMP levels, opening of HCN channels and disconnection of PFC networks (right). [Images courtesy of Amy Arnsten, Yale University]

The model suggests that this shunt, or short-circuit, which attenuates the propagation of synaptic signals to the rest of the neuron, can be prevented by phosphodiesterase or adrenergic stimulation, since both lower cAMP levels and thereby close the HCN channels (PDE degrades cAMP, while α2A-AR ligands activate Gi proteins that block cAMP synthesis). In fact, using immunohistochemical analysis, Wang and colleagues found that HCN channels and α2A-ARs are colocalized in the dendrites of primate PFC. “We found that those channels are heavily concentrated on dendritic spines, particularly on the neck of the spines, which is key for gating. Nothing can get through to the cell without going through that neck, so if the [HCN] channels are open, the information can’t flow and the networks can’t connect,” said Arnsten.

Is This a Link Between DISC1 and Working Memory?
Ever since scientists found a translocation in the gene for DISC1 that strongly associates with schizophrenia and other psychiatric disorders, the gene and its protein product have come in for intense scrutiny. Though the biology of DISC1 has not been exhaustively explored, one path of investigation has suggested that DISC1 mutations compromise the transport of essential protein cargo down neuronal axons (see SRF related news story). Another posits that DISC1 modulates key signal transduction pathways that, if perturbed, might alter neuronal activity and circuitry (see SRF related news story). Finally, there is a very tentative link to working memory, in that researchers have found working memory deficits in mice with a naturally occurring DISC1 mutation (see SRF related news story).

These latest findings are then potentially relevant to schizophrenia and other major psychiatric disorders linked to DISC1, which can activate PDE4B. “During stress, cAMP levels increase and there is a loss of prefrontal function. This suggests that people with DISC1 mutations would be particularly susceptible to network collapse during exposure to stress,” said Arnsten. In fact, the researchers were able to demonstrate this experimentally in the primate model by administering etazolate, a phosphodiesterase inhibitor, which is similar to “having a DISC1 mutation,” said Arnsten. Etazolate suppressed delay-related PFC firing. If this model is confirmed by further experimentation, it might validate a new therapeutic approach (which the researchers have begun to patent) for cognitive deficits in schizophrenia, namely, blocking HCN channels.—Tom Fagan and Hakon Heimer.

Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AFT. Alpha2A-adrenoreceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007, April 20;129:397-410. Abstract

Comments on News and Primary Papers
Comment by:  Joseph Friedman
Submitted 11 May 2007 Posted 11 May 2007

Cognitive symptoms have emerged as an independent feature...  Read more

View all comments by Joseph Friedman
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