A Novel CCK Receptor Regulates the Long-term Potentiation of Inhibition in the Auditory Cortex

Description

Activities of glutamatergic cholecystokinin positive (CCK+) neurons in the entorhinal cortex induce long-term potentiation (LTP) and promote neuroplasticity in the auditory cortex [1-3] and the hippocampus [4]. Thalamocortical and corticothalamic neurons can also release CCK that enables LTP in thalamocortical and corticothalamic projections when they are activated by high-frequency stimulation (HFS) [5]. However a prominent population of CCK+ neurons in the cortex have been identified as GABAergic. We recently discovered that, in stark contrast to the conventional view, these GABAergic CCK+ neurons seem to be capable of activating a novel type of CCK candidate receptors (e.g. not A or B type) to induce inhibitory long-term potentiation (iLTP, Fig. 1,2). Thus, the objectives of the present study are to confirm this preliminary finding and further explore the iLTP hypothesis by examining: 1) the enhancement of inhibitory GABAergic inputs or iLTP, after HFS of the GABAergic CCK neurons; 2) whether iLTP can be produced after local application of CCK on CCKAR/BR-/- (CCKAB-KO for short) mice, and whether HFS of inhibitory neurons after virus injection and functional rescue can induce iLTP on CCK-KO and CCKAB-KO mice; 3) the similarity to the known CCK receptors, AR and BR of all existing GPCRs based on their protein structure and the co-localization the GABAergic CCK terminal and GABAARs with each of 10 shortlisted receptors; 4) whether the anatomically-identified, final candidate receptor is a CCK receptor; 5) whether overexpression of the candidate receptor can enhance iLTP. To our knowledge, unlike excitatory LTP, the general phenomenon of long term inhibitory synaptic modulation in the mammalian CNS has never been clearly elucidate. Our hypothesis, for the first time, describes an original and robust molecular mechanism on how the inhibitory circuit participates in the formation of long-term synaptic plasticity. The most impactful aspect of this research, however, resides with our ability in determining the nature of a third CCK candidate receptor subtype, which may has far reaching implication in future drug development and disease therapies.