The muscarinic M1 receptor modulates associative learning and memory in psychotic disorders

Abstract

Background: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M₁ receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M_1/4 receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M₁ receptor signaling in psychotic disorders.

Methods: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M₁ antagonist biperiden, while performing the paired associated learning task. M₁ binding potentials (BP_ND) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using ¹²³I-IDEX single photon emission computed tomography.

Results: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M₁ antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M₁ receptor binding during learning, with no association found with M₁ receptor binding in the DLPFC. M₁ receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.

Conclusion: The current study is the first to show differences in M₁ receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M₁ receptor reserve in temporal-limbic areas.

Fig. 1

Overview of the paired associate learning task (PAL) task as performed during scanning. The initial phase of the task was the learning phase. Each white box opened for 3s displaying a figure and subjects had to try to remember the figure and it's location. After all boxes have opened and closed each figure appeared in the center of the screen and subjects had to select the box in which it originally appeared. The same figure place associations were presented twice. During the control phase subjects had to select the box to which the arrow was pointing.

Fig. 2

A. Overview of clusters showing a significant group by drug interaction during the learning phase, with both groups showing significantly increased functional activation in the right superior temporal gyrus, left parahippocampal gyrus, and left precuneus under biperiden compared to placebo. In the subjects diagnosed with a psychotic disorder this hyperactivation was significantly greater compared to controls. B. Overview of clusters showing a significant group by drug interaction effect during the memory phase. Patients diagnosed with a psychotic disorder had significantly increased activation in these clusters whereas controls showed attenuation of activation. All findings were corrected for IQ, accuracy and multiple comparisons. R: right; L: left.

Fig. 3

A: A1&A2: Lower hippocampal M₁ binding significantly predicted a smaller functional response to biperiden in left inferior temporal gyrus, fusiform gyrus, and parahippcampal gyrus during learning suggesting less M₁ reserve to elicit functional response during learning in the subjects with psychotic disorder. A3: Activation in significant clusters associated with hippocampal M₁ binding in the subjects with a psychotic disorder plotted out for both groups. B: B1&B2: Lower M₁ binding in the DLPFC significantly predicted a decreased functional response in the left cingulate gyrus in to biperiden during the memory phase. Lower DLPFC M₁ binding as associated with lower ability to functionally activate this area after biperiden. B3: Activation in significant clusters associated with DLPFC M₁ binding in the subjects diagnosed with a psychotic disorder plotted out for both groups. k: cluster size, pla: placebo bip: biperiden.