Frequency-dependent gating of feedforward inhibition in thalamofrontal synapses

Thalamic recruitment of feedforward inhibition is known to enhance the fidelity of the receptive field by limiting the temporal window during which cortical neurons integrate excitatory inputs. Feedforward inhibition driven by the mediodorsal nucleus of the thalamus (MD) has been previously observed, but its physiological function and regulation remain unknown. Accumulating evidence suggests that elevated neuronal activity in the prefrontal cortex is required for the short-term storage of information. Furthermore, the elevated neuronal activity is supported by the reciprocal connectivity between the MD and the medial prefrontal cortex (mPFC). Therefore, detailed knowledge about the synaptic connections during high-frequency activity is critical for understanding the mechanism of short-term memory. In this study, we examined how feedforward inhibition of thalamofrontal connectivity is modulated by activity frequency. We observed greater short-term synaptic depression during disynaptic inhibition than in thalamic excitatory synapses during high-frequency activities. The strength of feedforward inhibition became weaker as the stimulation continued, which, in turn, enhanced the range of firing jitter in a frequency-dependent manner. We postulated that this phenomenon was primarily due to the increased failure rate of evoking action potentials in parvalbumin-expressing inhibitory neurons. These findings suggest that the MD-mPFC pathway is dynamically regulated by an excitatory-inhibitory balance in an activity-dependent manner. During low-frequency activities, excessive excitations are inhibited, and firing is restricted to a limited temporal range by the strong feedforward inhibition. However, during high-frequency activities, such as during short-term memory, the activity can be transferred in a broader temporal range due to the decreased feedforward inhibition.