Hippocampal and prefrontal cortical synaptic plasticity: prevention and reversal of the effects of subchronic NMDA receptor antagonism

  • Neugebauer, Nichole M (PD/PI)

Project: Research project

Project Details

Description

Cognitive impairment in schizophrenia (CIS) is usually the earliest manifestation of schizophrenia, the most enduring and treatment resistant dimension, and the most important predictor of functional outcome. While current atypical antipsychotic drugs (APDs), including lurasidone, improve some aspects of CIS in some patients, including declarative memory, a better understanding of the biological processes which contribute to this action is needed.

Structural and functional plasticity of dendritic spines at synapses of excitatory and inhibitory neurons in the hippocampus (HPC) and prefrontal cortex (PFC) are essential for adequate cognition, including learning and memory and a partial loss of spines in both regions has been demonstrated in schizophrenia. In a rodent model of CIS, subchronic administration of the N-methyl-D-aspartate antagonist, phencyclidine (scPCP) results in severe, enduring deficits in multiple cognitive domains, e.g. declarative and working memory, as tested by novel object recognition (NOR), an effect that is reversed by administration atypical APDs. Interestingly, the scPCP model also results in a reduction in the quantity of cortical spines that is prevented and restored by the atypical APD olanzapine.

Dr. Meltzer’s laboratory has shown that serotonin (5-HT)1A partial agonism and 5-HT7 antagonism plays a crucial role in the ability of the atypical APD, lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, to prevent and ameliorate the effect of scPCP on NOR and electrophysiological abnormalities in the PFC and HPC. My research will determine whether signaling through 5-HT1A and 5-HT7 receptors located on pyramidal neurons in the HPC and PFC influences molecular regulators of structural plasticity at excitatory synapses, a process that may underlie the neuroprotective and restorative actions of atypical APDs and the 5-HT1A and 5-HT7 ligands in this model of CIS. It is my expectation that these studies will facilitate the development of more efficacious therapies for treating CIS.
StatusFinished
Effective start/end date1/15/151/14/17

Funding

  • Brain & Behavior Research Foundation (23031)

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