top of page

Antipsychotic drugs

We have recently discovered a promising candidate biomarker of antipsychotic drug function in cortex. The overarching aim of this research project is to establish the validity of this biomarker, understand its mechanism, and test its disease relevance. Antipsychotic drugs are a class of small molecules that act on a diverse set of neuromodulatory receptors and reduce or ameliorate psychosis in patients. While the receptor binding profiles of most of these drugs are well established, it is still unclear how they influence brain function and what their treatment-relevant functional effects are. Psychosis can be characterized as a diminished ability of the brain to distinguish internally and externally generated activity patterns. In humans, conscious perception likely occurs in cortex. We were investigating mechanisms by which cortical circuits in the mouse distinguish self-generated feedback from externally generated input, and how this process is influenced by substances known to interfere with conscious perception, such as antipsychotic drugs. We discovered that a key set of clinically relevant antipsychotic drugs all selectively alter the ability of layer 5 excitatory neurons to distinguish externally and internally generated stimuli, and decorrelate the activity of layer 5 neurons in different cortical areas. These effects were absent or much reduced in other cortical layers. The aims of this research project are first, to improve upon our original measurement method to enable higher throughput and test a wide variety of antipsychotic and hallucinogenic compounds. Second, to determine the mechanisms underlying the decorrelation effect on layer 5 neurons by probing both the influence of antipsychotic drugs on local cortical circuitry as well as on cortico-striatal-thalamic loops. Third and last, to test whether the antipsychotic influence on cortical layer 5 neurons might be disease relevant by probing layer specific functional alterations in mouse models of schizophrenia. The relevance of this research is two-fold. First, if the decorrelation of layer 5 is indeed a biomarker of antipsychotic efficacy, this would be useful as a screen for antipsychotic efficacy of novel compounds. Second, we suspect that the alteration of layer 5 activity is indeed disease relevant and a core mechanism involved in the etiology of schizophrenia. Currently, we have no clear understanding of the circuit alterations in schizophrenia and cannot design targeted circuit interventions. Thus, should we be able to confirm the layer 5 biomarker of antipsychotic drugs and establish its mechanism, this research would have a directly translatable impact on antipsychotic drug discovery.


Reduction of layer 5 mediated long-range cortical communication by antipsychotic drugs
Reduction of layer 5 mediated long-range cortical communication by antipsychotic drugs
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits and in particular their ability to identify self-generated activity patterns is still largely unclear. Here we used widefield calcium imaging to determine the cell type specific functional effects of antipsychotic drugs in mouse dorsal cortex during visuomotor integration. By comparing cell type specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex are long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine, as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is an alteration of the activation of internal representations as a consequence of reduced long-range layer 5 mediated communication. ### Competing Interest Statement The authors have declared no competing interest.

bottom of page