Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits

Luke E. Sebel, Steven M. Graves, C. Savio Chan, D. James Surmeier

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D 2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics.

Original languageEnglish (US)
Pages (from-to)963-973
Number of pages11
JournalNeuropsychopharmacology
Volume42
Issue number4
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Funding Information:
This work was supported by NIMH P50 MH090963, NS34696, NS084735, and the JPB Foundation.

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