Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC53
Altered synaptic transmission in the CA3 region in a mouse model of mental retardation
K. K. Gill1, P. Saintot1, A. D. Powell1, J. G. Jefferys1
1. Neuronal Networks Group, University of Birmingham, Birmingham, United Kingdom.
Mental retardation (MR) affects 2-3% of the population, with X-linked mutations a common cause of moderate to severe MR (Ramakers, 2002). OPHN-1 (Ophn-1 in mice) is one of the genes implicated in X-linked mental retardation (XLMR), encoding oligophrenin-1, a RhoGAP protein. Loss of function mutations affect Rho GTPase-dependent signalling pathways and alter actin cytoskeleton dynamics which affect vesicle dynamics and dendritic spine structure, the site of neurotransmission (Khelfaoui et al., 2007). Recent research has suggested oligophrenin-1 regulates endocytosis of synaptic vesicles (Khelfaoui et al., 2009). At present, no drug treatment is available for MR and treatment is primarily through educational therapy. The mechanisms underlying the cognitive decline in MR are poorly understood and better knowledge may enable better pharmacological intervention. Ophn-1 mice (male,3-10 weeks old) were anaesthetised by intraperitoneal injection of medetomidine (1mg/kg) and ketamine (76mg/kg). Values are expressed as mean±S.E.M, analysed by ANOVA, Mann-Whitney U or Student’s t-test. To investigate the role of oligophrenin-1 in synaptic function, extracellular postsynaptic field potentials (PSPs) were recorded from the stratum radiatum in the CA3c region of the hippocampus and evoked by stimulating the hilus. The amplitude of the PSP increased with larger stimulus intensities; Ophn-1-/y responses were smaller than Ophn-1+/y slices (p=0.011, n=5&12, respectively). To investigate the role of oligophrenin-1 in secretory vesicle availability at frequencies relevant to cognition, synaptic responses to repetitive stimuli (40 stimuli at 33Hz) were examined. Ophn-1-/y slices showed less potentiation than Ophn-1+/y slices (p=0.001, n=5&12, respectively). To further elucidate the synaptic changes associated with oligophrenin-1 loss of function, whole cell patch-clamp recordings were used to examine synaptic activity of CA3c pyramidal neurons. The frequency of spontaneous EPSCs and IPSCs (excitatory postsynaptic potentials and inhibitory postsynaptic potentials) was lower in Ophn-1-/y than Ophn-1+/y neurons (sEPSCs: 1.67±0.37 Hz, n=9; 6.91±1.50 Hz n=8, p=0.003; sIPSCs: 8.78±0.81 Hz, n=7; 12.63±0.76 n=7, p=0.009, respectively). The ability of synapses to follow high frequency stimulation (33Hz) was examined. IPSCs built up with successive stimuli, reaching a steady level within 10 stimuli in Ophn-1+/y neurons; IPSC facilitation was much weaker in Ophn-1−/y than Ophn-1+/y neurons. (p=0.001, n=9&17, respectively). This study demonstrates a synaptic malfunction which may be due to altered vesicle dynamics at the presynaptic terminal as a result of reduced readily releasable pool size or impaired endocytosis, although alterations in AMPA receptor dynamics or long term depression may also contribute (Khelfaoui et al., 2009).
Where applicable, experiments conform with Society ethical requirements