GABAergic Cholecystokinin Enhances the Local Inhibitory Effect in the Auditory Cortex

Description

The entorhinal cortex enables neuroplasticity of the auditory cortex throughcholecystokinin (CCK) [1]. With high-frequency stimulation, the thalamocortical andcorticothalamic neurons release CCK that enables thalamocortical and corticothalamiclong-term potentiation (LTP). We recently found that high-frequency activation is thecompulsory condition for glutamatergic CCK neurons to release CCK (Figs. 2-3 andunpublished).The third population of and also mostly-attended cortex-related CCK neurons foundover the past few decades are the GABAergic CCK neurons in the neocortex. In thepresent study, we aim to examine whether: 1) high-frequency activation of GABAergicCCK neurons induces CCK release; and 2) whether the released CCK enhancesGABAergic inputs to the pyramidal neurons.In order to facilitate our aim we will generate two transgenic mice - a GABA-CCK-Crestrain in which only GABAergic CCK neurons express the Cre recombinase and aGABA-CCK-CreER strain in which CCK is knocked-out only and the CreERrecombinase is inserted into GABAergic CCK neurons. After transfecting the neuronswith AAV-DIO-ChR2-eYFP virus we will specifically activate the GABAergic CCKneurons by employing optogenetics. Thereafter, examination of whether CCK is releasedfrom GABAergic CCK neurons after high-frequency stimulation will be explored. Wewill examine whether CCK is released from GABAergic CCK neurons only after high-frequencystimulation. Enhanced inhibition of GABAergic neurons is expected whenCCK is released in GABA-CCK-Cre mouse. The enhanced inhibition can be detected bya probe stimulus consisting of single-pulse laser stimulation and an auditory stimuluswith an interval in between. Neuronal responses to the auditory stimulus will beinhibited by laser-activated GABAergic neurons. Further confirmation of enhancedinhibition will stem from the increased inhibitory response in the membrane potential ofthe pyramidal neuron with in vivo intracellular recording on the anesthetized mouse.Before the above mouse lines are generated, examination of the inhibition of GABAergicinputs to pyramidal neurons can be enhanced after high-frequency laser stimulation ofGABAergic neurons, using our existing Viaat-Cre, CCK-Cre and CCK-CreER (CCK-/-)mice. For CCK-Cre and CCK-/- mice, we’ll inject a virus into the superficial layers toavoid deep-layer pyramidal CCK neurons.The long-term impacts of the present study are two-fold: 1) potentially unveil themechanism of neuroplasticity of the inhibitory circuit in the neocortex; and 2) throughthe linkage of the high-frequency firing of GABAergic CCK neurons with plasticity ofinhibitory circuits provide an important angle for drug development to treat epilepsythrough enhancement of the inhibition. ?