UC San Diego

Neurotransmitter switching (NTS) is a form of neuroplasticity in which a neuron loses the neurotransmitter it was expressing and gains a new one in response to external stimuli causing sustained changes in brain activity. Preliminary data from our laboratory have demonstrated that phencyclidine (PCP), a drug of abuse also known as angel dust, induces a glutamate-to-GABA transmitter switch in prelimbic cortex pyramidal neurons, and that this switch in transmitter is causally linked to the appearance of PCP-induced cognitive deficits. Clozapine is an antipsychotic medication that prevents PCP-induced increase in prefrontal cortex activity and has been shown to rescue PCP-induced cognitive deficits. In this thesis, I investigated whether clozapine administration can be used to reverse the NTS caused by PCP. To permanently label glutamatergic neurons, even when they change their transmitter identity, I used a mouse line expressing both VGLUT1-cre and a Cre-dependent mCherry reporter. Mice received daily injections of PCP or saline as a control for 10 days followed by an additional 2 weeks of treatment with either clozapine or vehicle as a control. After sacrifice, prelimbic cortex sections were immunostained for the inhibitory transmitter GABA and the number of neurons co-expressing mCherry and GABA across the experimental groups was counted. In mice treated with both PCP and clozapine the number of mCherry+/GABA+ neurons was significantly reduced as compared to that of mice treated with only PCP and was comparable to that of control. This result demonstrates that clozapine can successfully reverse the glutamate-to-GABA NTS induced by PCP.