Gsx1 expression defines neurons required for prepulse inhibition

• Published in: Molecular psychiatry 2015-08, Vol.20 (8), p.974-985
• Main Authors: Bergeron, S A, Carrier, N, Li, G H, Ahn, S, Burgess, H A
• Format: Article
• Language: English
• Subjects: 14/19; 14/32; 14/35; 45/43; 45/44; 45/70; 631/208; 631/378; 64/116; Ablation; Animal models; Animals; Animals, Genetically Modified; Antipsychotics; Auditory Perception - physiology; Behavioral Sciences; Biological Psychology; Brain - embryology; Brain - physiology; Brain stem; Childrens health; Clinical trials; Cloning; Cognitive ability; Danio rerio; Developmental stages; Forebrain; Gene expression; Genetic aspects; Genetic screening; Genomics; Glutamatergic transmission; Glutamic Acid - metabolism; Health aspects; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; In Situ Hybridization; Information processing; Medicine; Medicine & Public Health; Mental disorders; Mice, Knockout; Microscopy, Confocal; Microscopy, Fluorescence; Neurons; Neurons - physiology; Neurosciences; Optogenetics; original-article; Pharmacotherapy; Prepulse Inhibition - physiology; Psychiatry; Psychosis; Reflex, Startle - physiology; Risk factors; Schizophrenia; Startle response; Synapses; Synaptogenesis; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2014.106

In schizophrenia, cognitive overload is thought to reflect an inability to suppress non-salient information, a process which is studied using prepulse inhibition (PPI) of the startle response. PPI is reduced in schizophrenia and routinely tested in animal models and preclinical trials of antipsychotic drugs. However, the underlying neuronal circuitry is not well understood. We used a novel genetic screen in larval zebrafish to reveal the molecular identity of neurons that are required for PPI in fish and mice. Ablation or optogenetic silencing of neurons with developmental expression of the transcription factor genomic screen homeobox 1 (gsx1) produced profound defects in PPI in zebrafish, and PPI was similarly impaired in Gsx1 knockout mice. Gsx1-expressing neurons reside in the dorsal brainstem and form synapses closely apposed to neurons that initiate the startle response. Surprisingly, brainstem Gsx1 neurons are primarily glutamatergic despite their role in a functionally inhibitory pathway. As Gsx1 has an important role in regulating interneuron development in the forebrain, these findings reveal a molecular link between control of interneuron specification and circuits that gate sensory information across brain regions.