RESUMO
Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8-Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Deleção Cromossômica , Emoções , Memória , MicroRNAs/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Tálamo/fisiopatologia , Animais , Comportamento Animal , Cromossomos de Mamíferos/genética , Medo , Técnicas de Silenciamento de Genes , Glutamatos/metabolismo , Camundongos , MicroRNAs/genética , Neurônios/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores de Dopamina D2/metabolismo , Sinapses/metabolismo , Transmissão SinápticaRESUMO
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.
Assuntos
Córtex Auditivo/fisiopatologia , Vias Auditivas/fisiopatologia , Síndrome de DiGeorge/genética , MicroRNAs/genética , Transtornos Psicóticos/genética , Tálamo/fisiopatologia , Idade de Início , Animais , Antipsicóticos/farmacologia , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Vias Auditivas/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Western Blotting , Síndrome de DiGeorge/fisiopatologia , Síndrome de DiGeorge/psicologia , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/genética , Deleção de Genes , Haploinsuficiência , Humanos , Camundongos , MicroRNAs/metabolismo , Vias Neurais , Optogenética , Técnicas de Patch-Clamp , Fenótipo , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/psicologia , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Dopamina D2/genética , Reflexo de Sobressalto , Esquizofrenia/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
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.
Assuntos
Síndrome da Deleção 22q11/genética , Córtex Auditivo/metabolismo , Haploinsuficiência , Proteínas de Ligação a RNA/genética , Receptores de Dopamina D2/biossíntese , Esquizofrenia/genética , Tálamo/metabolismo , Síndrome da Deleção 22q11/tratamento farmacológico , Animais , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Camundongos , Camundongos Mutantes , MicroRNAs/metabolismo , Receptores de Dopamina D2/genética , Esquizofrenia/tratamento farmacológico , Transmissão Sináptica/genéticaRESUMO
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.
Assuntos
Córtex Auditivo/fisiologia , Canais de Cálcio Tipo T/fisiologia , Córtex Cerebral/fisiologia , Vias Neurais/fisiologia , Tálamo/fisiologia , Animais , Fenômenos Eletrofisiológicos/fisiologia , Potenciais Evocados/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Reação em Cadeia da Polimerase , Sinapses/fisiologiaRESUMO
Cortical maps in sensory cortices are plastic, changing in response to sensory experience. The cellular site of such plasticity is currently debated. Thalamocortical (TC) projections deliver sensory information to sensory cortices. TC synapses are currently dismissed as a locus of cortical map plasticity because TC synaptic plasticity is thought to be limited to neonates, whereas cortical map plasticity can be induced in both neonates and adults. However, in the auditory cortex (ACx) of adults, cortical map plasticity can be induced if animals attend to a sound or receive sounds paired with activation of cholinergic inputs from the nucleus basalis. We now show that, in the ACx, long-term potentiation (LTP), a major form of synaptic plasticity, is expressed at TC synapses in both young and mature mice but becomes gated with age. Using single-cell electrophysiology, two-photon glutamate uncaging, and optogenetics in TC slices containing the auditory thalamus and ACx, we show that TC LTP is expressed postsynaptically and depends on group I metabotropic glutamate receptors. TC LTP in mature ACx can be unmasked by cortical disinhibition combined with activation of cholinergic inputs from the nucleus basalis. Cholinergic inputs passing through the thalamic radiation activate M1 muscarinic receptors on TC projections and sustain glutamate release at TC synapses via negative regulation of presynaptic adenosine signaling through A1 adenosine receptors. These data indicate that TC LTP in the ACx persists throughout life and therefore can potentially contribute to experience-dependent cortical map plasticity in the ACx in both young and adult animals.
Assuntos
Córtex Auditivo/fisiologia , Período Crítico Psicológico , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Tálamo/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de ÓrgãosRESUMO
Long-term synaptic enhancements in cortical and thalamic auditory inputs to the lateral nucleus of the amygdala (LAn) mediate encoding of conditioned fear memory. It is not known, however, whether the convergent auditory conditioned stimulus (CSa) pathways interact with each other to produce changes in their synaptic function. We found that continuous paired stimulation of thalamic and cortical auditory inputs to the LAn with the interstimulus delay approximately mimicking a temporal pattern of their activation in behaving animals during auditory fear conditioning resulted in persistent potentiation of synaptic transmission in the cortico-amygdala pathway in rat brain slices. This form of input timing-dependent plasticity (ITDP) in cortical input depends on inositol 1,4,5-trisphosphate (InsP(3))-sensitive Ca(2+) release from internal stores and postsynaptic Ca(2+) influx through calcium-permeable kainate receptors during its induction. ITDP in the auditory projections to the LAn, determined by characteristics of presynaptic activity patterns, may contribute to the encoding of the complex CSa.
Assuntos
Tonsila do Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Inositol 1,4,5-Trifosfato/metabolismo , Vias Neurais/fisiologia , Ratos , Receptores de Ácido Caínico/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Thalamocortical (TC) projections provide the major pathway for ascending sensory information to the mammalian neocortex. Arrays of these projections form synaptic inputs on thalamorecipient neurons, thus contributing to the formation of receptive fields (RFs) in sensory cortices. Experience-dependent plasticity of RFs persists throughout an organism's life span but in adults requires activation of cholinergic inputs to the cortex. In contrast, synaptic plasticity at TC projections is limited to the early postnatal period. This disconnect led to the widespread belief that TC synapses are the principal site of RF plasticity only in neonatal sensory cortices, but that they lose this plasticity upon maturation. Here, we tested an alternative hypothesis that mature TC projections do not lose synaptic plasticity but rather acquire gating mechanisms that prevent the induction of synaptic plasticity. Using whole-cell recordings and direct measures of postsynaptic and presynaptic activity (two-photon glutamate uncaging and two-photon imaging of the FM 1-43 assay, respectively) at individual synapses in acute mouse brain slices that contain the auditory thalamus and cortex, we determined that long-term depression (LTD) persists at mature TC synapses but is gated presynaptically. Cholinergic activation releases presynaptic gating through M(1) muscarinic receptors that downregulate adenosine inhibition of neurotransmitter release acting through A(1) adenosine receptors. Once presynaptic gating is released, mature TC synapses can express LTD postsynaptically through group I metabotropic glutamate receptors. These results indicate that synaptic plasticity at TC synapses is preserved throughout the life span and, therefore, may be a cellular substrate of RF plasticity in both neonate and mature animals.
Assuntos
Córtex Cerebral/citologia , Depressão Sináptica de Longo Prazo/fisiologia , Terminações Pré-Sinápticas/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/citologia , Animais , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Glutamatos/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/genética , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Compostos de Piridínio/metabolismo , Compostos de Amônio Quaternário/metabolismo , Receptor A1 de Adenosina/deficiência , Transmissão Sináptica/genéticaRESUMO
Despite being substantially outnumbered by intracortical inputs on thalamorecipient neurons, thalamocortical projections efficiently deliver acoustic information to the auditory cortex. We hypothesized that thalamic projections may achieve effectiveness by forming synapses at optimal locations on dendritic trees of cortical neurons. Using two-photon calcium imaging in dendritic spines, we constructed maps of active thalamic and intracortical inputs on dendritic trees of thalamorecipient cortical neurons in mouse thalamocortical slices. These maps revealed that thalamic projections synapse preferentially on stubby dendritic spines within 100 microm of the soma, whereas the locations and morphology of spines that receive intracortical projections have a less-defined pattern. Using two-photon photolysis of caged glutamate, we found that activation of stubby dendritic spines located perisomatically generated larger postsynaptic potentials in the soma of thalamorecipient neurons than did activation of remote dendritic spines or spines of other morphological types. These results suggest a novel mechanism of reliability of thalamic projections: the positioning of crucial afferent inputs at optimal synaptic locations.