Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice

Abstract

Heterozygous (HZ) missense mutations in the gene encoding syntaxin binding protein 1 (Stxbp1 or Munc18-1), a presynaptic protein essential for neurotransmitter release, causes early infantile epileptic encephalopathy, abnormal brain structure and mental retardation in humans. Here we investigated whether the mouse model mimics symptoms of the human phenotype. The effects of the deletion of munc18-1 were studied in HZ and wild-type (WT) mice based on heart rate (HR) and its variability (HRV) as independent measures to expand previous behavioral results of enhanced anxiety and impaired emotional learning suggesting mild cognitive impairments. HR responses were assessed during novelty exposure, during the expression and extinction of conditioned tone-dependent fear and during the diurnal phase. Novelty exposure yielded no differences in activity patterns between the two genotypes, while maximum HR differed significantly (WT: 770 bpm; HZ: 790 bpm). Retention tests after both auditory delay and trace fear conditioning showed a delayed extinction of the conditioned HR response in HZ mice compared to WT mice. Since the HR versus HRV correlation and HR dynamics assessed by nonlinear methods revealed similar function in HZ and WT mice, the higher HR responses of munc18-1 HZ mice to different emotional challenges cannot be attributed to differences in autonomic nervous system function. Thus, in contrast to the adverse consequences of deletion of a single allele of munc18-1 in humans, C57BL/6J mice show enhanced anxiety responses based on HR adjustments that extend previous results on the behavioral level without support of cognitive impairment, epileptic seizures and autonomic dysregulation.

Keywords: ANOVA; ANS; Autonomic measures; CS; Coping style; DFA; Diurnal changes; ECG; Fear conditioning; HR; HRV; HZ; Heart rate variability; Nonlinear analysis; PNS; PTSD; RMSSD; SNAP (Soluble NSF Attachment Protein) Receptor; SNARE; SNS; SPL; US; WT; analysis of variance; autonomic nervous system; beats per minute; bpm; conditioned stimulus; detrended fluctuation analysis; electrocardiogram; heart rate; heart rate variability; heterozygous; parasympathetic nervous system; posttraumatic stress disorder; root mean square successive difference; sound pressure level; sympathetic nervous system; unconditioned stimulus; wild-type.