Yumi Munemoto

Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex

We examined the regulation of the acoustic startle response in mutant mice of the N‐methyl‐d‐aspartate (NMDA)‐ and δ‐subtypes of the glutamate receptor (GluR) channel, which play important roles in neural plasticity in the forebrain and the cerebellum, respectively. Heterozygous mutant mice with reduced GluRε2 subunits of the NMDA receptor showed strongly enhanced startle responses to acoustic stimuli. On the other hand, heterozygous and homozygous mutation of the other NMDA receptor GluRε subunits exerted no, or only small effects on acoustic startle responses. The threshold of the auditory brainstem response of the GluRε2‐mutant mice was comparable to that of the wild‐type littermates. The primary circuit of the acoustic startle response is a relatively simple oligosynaptic pathway located in the lower brainstem, whilst the expression of GluRε2 is restricted to the forebrain. We thus suggest that the NMDA receptor GluRε2 subunit plays a role in the regulation of the startle reflex. Ablation of the cerebellar Purkinje cell‐specific δ2 subunit of the GluR channel exerted little effect on the acoustic startle response but resulted in the enhancement of prepulse inhibition of the reflex. Because inhibition of the acoustic startle response by a weak prepulse is a measure of sensorimotor gating, the process by which an organism filters sensory information, these observations indicate the involvement of the cerebellum in the modulation of sensorimotor gating.

The N-methyl-d-aspartate (NMDA)-type glutamate receptor GluRε2 is important for delay and trace eyeblink conditioning in mice

It has been proposed that the N-methyl-d-aspartate (NMDA)-type glutamate receptor (GluR) plays an important role in synaptic plasticity, learning, and memory. The four GluRepsilon (NR2) subunits, which constitute NMDA receptors with a GluRzeta (NR1) subunit, differ both in their expression patterns in the brain and in their functional properties. In order to specify the distinct participation of each of these subunits, we focused on the GluRepsilon2 subunits, which are expressed mainly in the forebrain. We investigated delay and trace eyeblink conditioning in GluRepsilon2 heterozygous mutant mice whose content of GluRepsilon2 protein was decreased to about half of that in wild-type mice. GluRepsilon2 mutant mice exhibited severe impairment of the attained level of conditioned response (CR) in the delay paradigm, for which the cerebellum is essential and modulation by the forebrain has been suggested. Moreover, GluRepsilon2 mutant mice showed no trend toward CR acquisition in the trace paradigm with a trace interval of 500 ms, in which the forebrain is critically involved in successful learning. On the other hand, the reduction of GluRepsilon2 proteins did not disturb any basic sensory and motor functions which might have explained the observed impairment. These results are different from those obtained with GluRepsilon1 null mutant mice, which attain a normal level of the CR but at a slower rate in the delay paradigm, and showed a severe impairment in the trace paradigm. Therefore, the NMDA receptor GluRepsilon2 plays a more critical role than the GluRepsilon1 subunit in classical eyeblink conditioning.

Hearing results for ossicular reconstruction using a cartilage-connecting hydroxyapatite prosthesis with a spearhead.

Objective: Assessment of the efficacy of ossicular reconstruction using a cartilage-connecting hydroxyapatite prosthesis designed with a spearhead to reduce extrusion and dislocation of the implant. Patients: All patients undergoing ossicular reconstruction after chronic ear surgery, connecting the cartilage to the prosthesis, with a minimum of 1 year of postoperative follow-up. Main Outcome Measures: Postoperative change in pure-tone averages. Air-bone gap closures, and implant extrusion rates. Results: Overall mean pure-tone averages improved by 12.2 dB (ranged between −40 and 60 dB). In total, 68.4% of the patients achieved an air-bone gap less than 20 dB. Gains in the mean air conduction thresholds were 9.5 dB in cases of partial ossicular reconstruction and 14.9 dB in cases with total ossicular reconstruction (p < 0.05). The overall extrusion rate was 4.21%. Conclusion: The cartilage-connecting hydroxyapatite prosthesis with a spearhead was found to restore hearing to a satisfactory level. The extrusion rate was relatively low. The cartilage-connecting hydroxyapatite prosthesis with a spearhead is an effective ossicular implant and offers an attractive alternative for ossicular reconstruction, particularly for total ossicular reconstructions.

Auditory pathway and auditory brainstem response in mice lacking NMDA receptor ϵ1 and ϵ4 subunits

Abstract There is considerable evidence that the N -methyl- d -aspartate receptor ((NMDAR) is a component of excitatory amino acid synapses in the ascending auditory pathway. The availability of mice that are defective in NMDAR ϵ 1 or NMDAR ϵ 4 subunit paves the way for investigations on the role of this receptor in auditory function. Non-radioactive in situ hybridization was used in the parent C57/6J wild strain to determine if these subunits are normally expressed in cochlear nucleus (CN) and superior olivary complex (SOC) and to confirm their absence in the respective mutant mice. Evoked auditory brainstem response (ABR) to normal acoustic stimulation was investigated to assess function. In situ hybridization revealed the expression of NMDAR ϵ 1 and ϵ 4 subunits mRNAs in major neuronal types in the CN and SOC of the wild type mice while ϵ 1 and ϵ 4 expression were absent in their respective mutant mice. The ABR threshold for the ϵ 1 mutant mice was similar to that of wild type mice however the threshold for the ϵ 4 mutant mice was significantly elevated. These results suggest a role for the NMDAR ϵ 4 in normal auditory functions while the NMDAR ϵ 1 may have a less critical function under normal conditions.

Brainstem auditory regions in mice: expression of nociceptin/orphanin FQ precursor mRNA in select neurons.

Nociceptin peptide-receptor system is known to be essential for the regulation of hearing ability. The mRNA for nociceptin precursor protein is highly expressed in the brainstem. We explored a detailed hybridohistochemical expression pattern of the nociceptin precursor mRNA in the mouse brainstem, and identified positive cells in several auditory brainstem nuclei. Positive cells were seen in the dorsal and ventral nuclei of the lateral lemniscus, the rostral periolivary region, the lateroventral and medioventral periolivary nuclei, the dorsal periolivary region, the superior paraolivary nucleus, and the external cortex and dorsal cortex of the inferior colliculus. Of these, the medioventral and lateroventral periolivary nuclei, the major sites of origin of olivocochlear bundle, were most populated by positive cells.

A subset of nociceptin/orphanin FQ receptor-expressing neurons in the anterior hypothalamic area, as revealed in mice with lacZ reporter gene.

Nociceptin/orphanin FQ (N/OFQ) is an endogenous peptide agonist for the opioid receptor homolog, N/OFQ receptor, and serves for the central control of autonomic functions. Morphological details including the cell types that may account for such N/OFQ functions, however, remain unclear. By using X-gal histochemistry for the detection of receptor-expressing cells at both light and electron microscopic levels, we examined the hypothalamus from the receptor-deficient mice bearing a lacZ insertional mutation in the N/OFQ receptor gene. The N/OFQ receptor reflected by lacZ expression was seen at high levels in the anterior hypothalamic area. With electron microscopy, lacZ expression was observed in a subset of neurons showing large cell size and indented nucleus.

THE HEARING RESULTS OF OUR OPERATIVE METHOD USING A CARTILAGE CONNECTING HYDROXYAPATITE PROSTHESIS WITH A SPEARHEAD

In 1992, we newly designed a cartilage connecting hydroxyapatite prosthesis with a spearhead. The concept of this new prosthesis is to avoid the extrusion and dislocation of hydroxyapatite prostheses. This new prosthesis has a spearhead on the top and the cartilage and prosthesis are connected to each other using this spearhead. In 1995, we established a database for the hearing results of all tympanoplasty cases. From this database we selected 302 cases who underwent tympanoplasty with the cartilage connecting hydroxyapatite prosthesis. When we cannot preserve the tendon of the tensor tympani muscle in a severely diseased middle ear, we use the cartilage connecting hydroxyapatite prosthesis. There are two types of prostheses. We select a partial type of prosthesis when stapes is present, and a total type when stapes is absent. We show the extrusion rate and hearing results. The postoperative hearing levels have remained stable throughout the 7 years observation period.