The beta crystallin gene (CRYBB2) is an ocular structural gene and mutation in this gene can cause cataract. Interestingly, beyond its role in the eye lens it is also associated with neuropsychiatric disorders, but how this gene may contribute to the symptoms of these disorders was unknown.
Scientists of the German Mouse Clinic and colleagues performed a comprehensive analysis of the behavioral and neuronal conditions in mutants and littermate controls of three mouse lines, Crybb2O377, Crybb2Philly and Crybb2Aey2, harboring different C-terminal mutations of the Crybb2 gene.
The influence of the mutations in the Crybb2 gene was evaluated using a behavioral test battery that included open field (OF), prepulse inhibition (PPI), social discrimination (SD), and spontaneous alternation in the Y-maze, to assess memory, sensory gating, locomotor activity and anxiety-related behavior. Several individual, allele-specific alterations in the three examined lines were identified, but only an alteration in PPI of the acoustic startle response (ASR) was consistently detectable across all, which is a measure of sensorimotor gating. PPI was increased in both Crybb2Philly and Crybb2O377, and decreased in Crybb2Aey2 mutant animals. Substantial evidence implicates PPI alterations in schizophrenia core symptoms. Because parvalbumin (PV) deficiency is known to affect the ASR and PPI in mice and is in addition another schizophrenia core symptom, PV positive cell numbers were analyzed in the brains of mutant and controls of the three investigated mouse lines. In both sexes and in all three lines the alterations in PPI corresponded to the changes in PV positive cell number in a specific region of the thalamus (Thalamic Reticular Nucleus, TRN) considered to be a hub for corticothalamic communications: both increased in the Crybb2Philly and Crybb2O377 mutants and decreased in the Crybb2Aey2 mutant animals. In different regions of interest, additional allele-specific alterations in PV+ cell numbers were found. Although each of the three investigated Crybb2 lines represents a different type of mutation, they all exhibit altered sensorimotor gating with parallel alterations in TRN PV+/GABAergic interneuron number.
These findings suggest that, in addition to the already established neuronal ASR/PPI circuitry, PV+/GABAergic interneurons of the TRN also contribute to the modulation of global PPI. This concurs with evidence showing profound irregularities in TRN PV+ interneurons in schizophrenia patients and suggest that a disturbance in CRYBB2 function might contribute to the development of neuropsychiatric diseases.
Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice. Heermann T, Garrett L, Wurst W, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Graw J, Hölter SM. Mol Neurobiol. 2018 Oct 6. doi: 10.1007/s12035-018-1365-5. [Epub ahead of print]