title: Clozapine and haloperidol differentially regulate dendritic spine formation and synaptogenesis in rat hippocampal neurons.
abstract: Antipsychotic drugs are the primary therapeutic treatment for schizophrenia. In addition to their dopaminergic/serotonergic function, atypical antipsychotics differ from conventional antipsychotics in the way they affect glutamatergic receptor function. A cellular correlate of this may be the modulation of dendritic spines (DS). Here, we demonstrate that in rat dissociated hippocampal neurons 1.0 microM clozapine administration increased DS-enriched protein spinophilin by 70%, increased post-synaptic protein shank1a puncta density by 26% and increased overall primary dendrite DS density by 59%. Filopodia and mushroom DS were particularly affected by clozapine. Conversely, 0.1 microM haloperidol decreased spinophilin protein by 40%, caused a 25% decrease in shank1a puncta and reduced the numbers of filopodia. In contrast, neither haloperidol nor clozapine induced any change in the levels of the pre-synaptic protein synapsin. This indicates that clozapine and haloperidol differentially regulate DS and post-synaptic plasticity. These findings may provide a molecular and cellular correlate to the superior therapeutic profile of clozapine when compared with haloperidol.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, UK. hmc39@cam.ac.uk
authors.forename: H M
authors.initials: HM
authors.lastname: Critchlow
authors.forename: P R
authors.initials: PR
authors.lastname: Maycox
authors.forename: J N
authors.initials: JN
authors.lastname: Skepper
authors.forename: O
authors.initials: O
authors.lastname: Krylova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D003024:Clozapine / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry / Q000379:methods; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D016704:Synapsins / Q000378:metabolism; D000099273:Neurabins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D003024:Clozapine; D006220:Haloperidol; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D016704:Synapsins; D000099273:Neurabins; C120531:Shank1 protein, rat