Adolescent Thalamo-Prefrontal Inhibition Leads to Changes in Intrinsic Prefrontal Network Connectivity.

ABSTRACT

Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long-lasting deficits in prefrontal-cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal-cortex maturation, it is unclear how inhibition of these projections affect prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in male/female mice from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (MD, NAc or callosal mPFC) twenty-four hours later using slice physiology. We chose mPFC and MD-projecting cells as they are largely distinguished by cortical layer (II/III versus V/VI, respectively) and NAc-projecting cells as they span both layers and therefore provide a within-layer comparison for the other two populations. We found a decrease in the frequency of excitatory and inhibitory currents in layer-II/III-nucleus-accumbens (NAc) and layer-V/VI-mediodorsal-thalamus-projecting neurons while layer-V/VI-NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal-cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).Significance Statement Connectivity between two brain regions, the thalamus and the prefrontal cortex, has been found to be reduced in patients with schizophrenia. Neuronal activity in thalamo-cortical projections is important for the proper development of sensory cortices. How thalamo-cortical activity regulates prefrontal cortex development is less well understood. Here, we show that decreasing activity in thalamo-prefrontal projections in mice during early adolescence alters synaptic connectivity to distinct neuronal projections within the prefrontal cortex that are already evident in adolescence. While some of these changes can be explained by reduced thalamo-cortical projections, other adaptations are intrinsic to the prefrontal cortex. These findings implicate adolescence as a critical period of cortical development and demonstrate this period as a potential target for therapeutic intervention.