Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4.

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/-) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/- mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.

Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm.

Schizophrenia (SZ) is a severe mental disorder affecting about 1 % of the human population. Patients show severe deficits in cognitive processing often characterized by an improper filtering of environmental stimuli. Independent genome-wide association studies confirmed a number of risk variants for SZ including several associated with the gene encoding the transcription factor 4 (TCF4). TCF4 is widely expressed in the central nervous system of mice and humans and seems to be important for brain development. Transgenic mice overexpressing murine Tcf4 (Tcf4tg) in the adult brain display cognitive impairments and sensorimotor gating disturbances. To address the question of whether increased Tcf4 gene dosage may affect cognitive flexibility in an auditory associative task, we tested latent inhibition (LI) in female Tcf4tg mice. LI is a widely accepted translational endophenotype of SZ and results from a maladaptive delay in switching a response to a previously unconditioned stimulus when this becomes conditioned. Using an Audiobox, we pre-exposed Tcf4tg mice and their wild-type littermates to either a 3- or a 12-kHz tone before conditioning them to a 12-kHz tone. Tcf4tg animals pre-exposed to a 12-kHz tone showed significantly delayed conditioning when the previously unconditioned tone became associated with an air puff. These results support findings that associate TCF4 dysfunction with cognitive inflexibility and improper filtering of sensory stimuli observed in SZ patients.

OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice.

Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases.

Kraepelin revisited: schizophrenia from degeneration to failed regeneration.

One hundred years after its conceptual definition as 'Dementia Praecox' by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients' cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.

"Early" vocal cord laterofixation for the treatment of bilateral vocal cord immobility.

OBJECTIVES: Vocal cord immobility (VCI) is commonly caused by a nonlaryngeal malignancy, thyroid surgery, or a presumed viral insult etc. The paralysis is often transient or temporary, thus the care of the patient should be optimized to avoid unnecessary diagnostic and therapeutic endeavours. This article reports on the result of the concept of early vocal cord laterofixation, which provides a minimally invasive solution to dyspnea in the critical early, potentially reversible, period of bilateral VCI. STUDY DESIGN: A prospective study of 25 consecutive patients (ages 33 to 81 years) who were diagnosed with a bilateral VCI. This condition had developed after thyroid surgery in 22 of the patients and after a blunt trauma of the neck in one case. In another case, a cricoarytenoid joint fixation was revealed, and aetiology remained unknown in one further patient. METHODS: The surgical procedure was performed endoscopically with a modification of Lichtenberger's endo-extralaryngeal suture lateralization technique. The abducted vocal cord position was achieved by inserting a non-resorbable thread around the vocal process and tying on to the prelaryngeal muscles. Regular spirometric measurements and radiological aspiration tests were conducted on the patients. RESULTS: Adequate postoperative airway was achieved in all patients except one. Significant spontaneous vocal cord medialization was observed in two cases within a year and in three patients in the second and the third year. Partial or complete vocal cord recovery was observed in 17 cases. Further voice improvement followed in 9 patients when the threads were removed, due to vocal cord medialization or recovery. The mild postoperative aspirations ceased in the first postoperative days in all cases except one. CONCLUSIONS: The concept of "early" laterofixation satisfies the important criteria: it can provide an immediate and long-lasting adequate airway, and it can be considered potentially reversible from the point of view of laryngeal functions. Thus the procedure is a reliable primary treatment for bilateral VCI.

Airway complication after thyroid surgery: minimally invasive management of bilateral recurrent nerve injury.

OBJECTIVES: After bilateral vocal cord paralysis, the consequent paramedian position usually necessitates tracheostomy for at least 6 months, when the paralysis is potentially reversible. In the present study a reversible endoscopic vocal cord laterofixation procedure was used instead of tracheotomy. STUDY DESIGN: Prospective study of 15 consecutive patients aged 33 to 73 years who suffered bilateral recurrent laryngeal nerve paralysis after thyroid surgery. METHODS: The operation was performed endoscopically with a special endo-extralaryngeal needle carrier instrument. Two ends of a monofilament nonresorbable thread were passed above and under the posterior third of the vocal cord and knotted on the prelaryngeal muscles, permitting the creation of an abducted vocal cord position. If movement of one or both vocal cords recovered, the suture was removed. Regular spirometric measurements and radiological aspiration tests were conducted on the patients. RESULTS: During the follow-up period of 3 to 40 months, airway stability was demonstrated in all but one patient. After the repeated lateralization procedure, this patient's breathing improved. Partial or complete vocal cord recovery was observed in eight patients. In six patients further voice improvement was achieved when the threads were removed after vocal cord medialization or recovery. Mild postoperative aspirations ceased in the first postoperative days. CONCLUSIONS: This management approach offers an alternative to tracheostomy in the early period of paralysis, avoids terminal loss of voice quality, and provides a "one-stage" solution for permanent bilateral recurrent nerve injuries.

Minimally invasive surgery for posterior glottic stenosis.

Posterior glottic stenosis most commonly results from prolonged endotracheal intubation. The tube causes decubitus and perichondritis with a consequent scar tissue formation in the posterior commissure that often limits the abduction of the vocal cords. Many different surgical methods are known for the treatment, but in most cases temporary tracheostomy is required. We recommend a minimally invasive method to avoid tracheostomy, which is a very inconvenient state for the patient. The scar of the posterior commissure is excised endoscopically with the CO2 laser, and a modification of the endoextralaryngeal vocal cord laterofixation described by Lichtenberger is used to lateralize 1 or both vocal cords until the posterior commissure is completely reepithelialized. In this article we report on the first 5 cases. All patients had satisfactory airways immediately after the laterofixation procedure, which proved to be stable later on as well. In the cases of moderate stenosis, further scarring was prevented, and after the healing of the mucosa in the posterior glottic area, the laterofixation sutures were removed. The vocal cord mobility was recovered in the cases in which the cricoarytenoid joint was not fixed. In 1 case of severe stenosis (bilateral cricoarytenoid joint fixation), the procedure yielded only partial improvement.

[Endolaryngeal lipoaugmentation of the vocal cords]. / Endolaryngealna lipoaugmentacja strun glosowych.

Unilateral vocal cord paralysis or the loss of vocal cord tissue results in incomplete glottic closure (internal-paresis) with a consequent hoarseness and poor voice quality. Improving glottic incompetence, instead of the previously used paraffin, teflon is a widely accepted and most commonly used substance at present for vocal cord medialization. Using intracordal teflon injection of for decades had proven that it has limitations and potential complications to the human body. Beside the well-known external "phono-surgical" methods, a wide interest has been shown in endolaryngeal phono-surgery and in finding the ideal and most available biocompatible substances for the procedure. Papers have been issued about the promising results of autologus fat injection for medialization of the paralyzed vocal fold in the early '90s. In this paper the authors report on their slightly modified endolaryngeal intracordal autologus fat injection procedure, and its promising results. The first three patients (a left side glottic paralysis, a bilateral internal paresis and a left side internal paresis) experienced an improvement in their voice right after the medialization procedure, what remained the same during the 11 months follow-up period. Using supraglottic jet ventilation during general anaesthesia provides very good access to the operating field. Monitoring of neuro-muscular block makes possible an intraoperative examination of glottic closure by the protective reflex of the larynx. Incouraged by this initial results the authors suggest the autologus fat as an easy available, ideal substance for increasing (augmenting) the loss of vocal cord tissue.

Tracheal substitution in dogs with reinforced Gore-Tex prosthesis.

Reinforced Gore-Tex prostheses were implanted into the trachea, above the bifurcation, in 11 dogs. The first 3 animals died within a few days, due to an inappropriate surgical technique. The remaining animals were subjected to an adequate surgical procedure and all survived for a period of at least several months, except one which died of an esophago-tracheal fistula after 6 weeks. Ingrowth of respiratory epithelium into the prostheses was observed 5 to 7 weeks postoperatively.