RESUMO
Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. Here we show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase-dependent adenosine production or A1-adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement of tone-discrimination abilities. We conclude that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.
Assuntos
Adenosina/metabolismo , Córtex Auditivo/metabolismo , Transdução de Sinais , 5'-Nucleotidase/metabolismo , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Agonistas do Receptor A1 de Adenosina/administração & dosagem , Antagonistas do Receptor A1 de Adenosina/administração & dosagem , Animais , Percepção Auditiva , Proteínas Ligadas por GPI/metabolismo , Camundongos , Plasticidade Neuronal , Piperidinas/administração & dosagem , Piridazinas/administração & dosagem , Receptor A1 de Adenosina/metabolismo , Tálamo/metabolismoRESUMO
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
Recent studies revealed that Abelson helper integration site 1 (AHI1) plays a role in brain development. However, little is known about the role of AHI1 in adult brain. To directly assess the role of AHI1 in the adult brain, we cloned full-length cDNA of rat AHI1 and observed prominent expression of AHI1 in the hypothalamus, which contributes mainly to the control of energy homeostasis. Furthermore, we demonstrated that food deprivation caused induction of AHI1 in the hypothalamus and subsequent re-feeding down-regulated AHI1 expression, suggesting the involvement of AHI1 in feeding control. Moreover, the expression of AHI1 was increased in serum-depleted Neuro2A cells and restored by subsequent insulin treatment. Furthermore, treatment in food-deprived rat with intraperitoneal glucose also reduced the increased AHI1 expression. These results demonstrate that AHI1 expression can be regulated through diet and suggest the novel role of AHI1 in feeding behavior.