ABSTRACT
Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.
Subject(s)
Auditory Cortex/physiopathology , Auditory Pathways/physiopathology , DiGeorge Syndrome/genetics , MicroRNAs/genetics , Psychotic Disorders/genetics , Thalamus/physiopathology , Age of Onset , Animals , Antipsychotic Agents/pharmacology , Auditory Cortex/drug effects , Auditory Cortex/metabolism , Auditory Pathways/drug effects , Behavior, Animal/drug effects , Blotting, Western , DiGeorge Syndrome/physiopathology , DiGeorge Syndrome/psychology , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/drug effects , Evoked Potentials, Auditory, Brain Stem/genetics , Gene Deletion , Haploinsufficiency , Humans , Mice , MicroRNAs/metabolism , Neural Pathways , Optogenetics , Patch-Clamp Techniques , Phenotype , Psychotic Disorders/physiopathology , Psychotic Disorders/psychology , RNA-Binding Proteins/genetics , Real-Time Polymerase Chain Reaction , Receptors, Dopamine D2/genetics , Reflex, Startle , Schizophrenia/metabolism , Thalamus/drug effects , Thalamus/metabolismABSTRACT
Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (Drd2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-Drd2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.
Subject(s)
22q11 Deletion Syndrome/genetics , Auditory Cortex/metabolism , Haploinsufficiency , RNA-Binding Proteins/genetics , Receptors, Dopamine D2/biosynthesis , Schizophrenia/genetics , Thalamus/metabolism , 22q11 Deletion Syndrome/drug therapy , Animals , Antipsychotic Agents/therapeutic use , Disease Models, Animal , Drug Resistance/genetics , Mice , Mice, Mutant Strains , MicroRNAs/metabolism , Receptors, Dopamine D2/genetics , Schizophrenia/drug therapy , Synaptic Transmission/geneticsABSTRACT
Brief sounds produce a period of suppressed responsiveness in the auditory cortex (ACx). This forward suppression can last for hundreds of milliseconds and might contribute to mechanisms of temporal separation of sounds and stimulus-specific adaptation. However, the mechanisms of forward suppression remain unknown. We used in vivo recordings of sound-evoked responses in the mouse ACx and whole-cell recordings, two-photon calcium imaging in presynaptic terminals, and two-photon glutamate uncaging in dendritic spines performed in brain slices to show that synaptic depression at thalamocortical (TC) projections contributes to forward suppression in the ACx. Paired-pulse synaptic depression at TC projections lasts for hundreds of milliseconds and is attributable to a switch between firing modes in thalamic neurons. Thalamic neurons respond to a brief depolarizing pulse with a burst of action potentials; however, within hundreds of milliseconds, the same pulse repeated again produces only a single action potential. This switch between firing modes depends on Ca(v)3.1 T-type calcium channels enriched in thalamic relay neurons. Pharmacologic inhibition or knockdown of Ca(v)3.1 T-type calcium channels in the auditory thalamus substantially reduces synaptic depression at TC projections and forward suppression in the ACx. These data suggest that Ca(v)3.1-dependent synaptic depression at TC projections contributes to mechanisms of forward suppression in the ACx.