Loss of Kv3.1 Tonotopicity and Alterations in cAMP Response Element-Binding Protein Signaling in Central Auditory Neurons of Hearing Impaired Mice

Abstract

The promoter for the kv3.1 potassium channel gene is regulated by a Ca 2ϩ -cAMP responsive element, which binds the transcription factor cAMP response element-binding protein (CREB). Kv3.1 is expressed in a tonotopic gradient within the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, where Kv3.1 levels are highest at the medial end, which corresponds to high auditory frequencies. We have compared the levels of Kv3.1, CREB, and the phosphorylated form of CREB (pCREB) in a mouse strain that maintains good hearing throughout life, CBA/J (CBA), with one that suffers early cochlear hair cell loss, C57BL/6 (BL/6). A gradient of Kv3.1 immunoreactivity in the MNTB was detected in both young (6 week) and older (8 month) CBA mice. Although no gradient of CREB was detected, pCREB-immunopositive cells were grouped together in distinct clusters along the tonotopic axis. The same pattern of Kv3.1, CREB, and pCREB localization was also found in young BL/6 mice at a time (6 weeks) when hearing is normal. In contrast, at 8 months, when hearing is impaired, the gradient of Kv3.1 was abolished. Moreover, in the older BL/6 mice there was a decrease in CREB expression along the tonotopic axis, and the pattern of pCREB labeling appeared random, with no discrete clusters of pCREB-positive cells along the tonotopic axis. Our findings are consistent with the hypothesis that ongoing activity in auditory brainstem neurons is necessary for the maintenance of Kv3.1 tonotopicity through the CREB pathway.

A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons

“…We therefore estimate that the 0.5-mM concentration of TEA used in our native tissue experiments would block approximately 60-80% of Kv3.1/3.2 channels. Kv3.1 channel expression has been shown to reduce with aging (von Hehn et al, 2004;Jung et al, 2005), and recent postmortem studies observed a reduction in Kv3.1 expression in the cortex of patients with schizophrenia (Yanagi et al, 2014). Thus, under conditions of pathologic reduction in Kv3 channel expression or function, which is likely to impair the normal FS phenotype of PV 1 interneurons, compounds like AUT1 have the potential to rescue normal function and thus have a therapeutic benefit in disorders like schizophrenia or age-related cognitive decline.…”

Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency

“…Kv3-mediated fast spiking is critical for sensory and reflex functions in the central nervous system, for instance, in the sound location by the auditory circuit and in stabilizing images on the retina by the vestibule-ocular reflex circuit (57)(58)(59). Fast-spiking GABAergic interneurons in the hippocampus and cortex play important roles in learning and memory, and are implicated in epilepsy, schizophrenia, and drug addiction (38,60).…”

Ionic and neuromodulatory regulation of burst discharge controls frequency tuning

“…One mechanism used to encode specific aspects of the signal involves multiple neuronal representations ('maps') that differentially encode the same stimulus, as found in the auditory and olfactory systems. This often involves gradients of expression of specific ion channels as observed in the ELL (Deng et al, 2005;Ellis et al, 2007b;Mehaffey et al, 2006;Smith et al, 2006) and in mammalian auditory processing, in particular in the auditory brainstem (Li et al, 2001;Perney and Kaczmarek, 1997;von Hehn et al, 2004).…”