Transient Inhibition of the Mediodorsal Thalamus During Early Adolescence Induces Hypofrontality and Social Memory Deficits in Young Adulthood.

Background: Dysconnectivity between the mediodorsal thalamus (MD) and medial prefrontal cortex (mPFC) during adolescence is linked to developmental and psychiatric disorders, as well as social behavioral deficits. However, the precise mechanisms that underlie these impairments remain elusive. Methods: We transiently inhibited MD activity with inhibitory DREADDs (HM4Di) in adolescent mice. Then, we examined the social behavior performance by a three-chamber social behavioral paradigm and neural excitability in both MD and mPFC neurons in adulthood with multiple approaches. Results: We revealed that this transient MD inhibition during adolescence led to impaired social memory in adulthood. The neuronal excitability of both MD and mPFC excitatory neurons decreased. Meanwhile, excitatory synaptic transmission in excitatory pyramidal neurons in the mPFC was impaired. In vivo calcium imaging showed a persistent reduction of general calcium activity in the mPFC. Unexpectedly, there were significant alterations in intrinsic excitability and synaptic function changes in somatostatin but not in parvalbumin interneurons. Conclusions: Our findings provide insights into the role of MD input activity in shaping the circuit and functional maturation of the mPFC that is critical for the normal development of social memory and abnormal deficits in psychiatric disorders.