Book of abstracts - British Neuroscience Association

58.01
Electrophysiological characterization of Oligophrenin-1 null
mouse, a mouse model of X-linked mental retardation
Saintot P-P, Powell A D, Jefferys J G R
Department of Neurophysiology, The Medical School, Division of
Neuroscience, University of Birmingham, Birmingham B15 2TT, UK.
Mental retardation (MR) is defined by an overall intellectual quotient
less than 70. It is the most common brain disease, with prevalence in
developed countries of approximately 2-3%. One of the first genes
identified in X-linked mental retardation (XLMR) was the OPHN-1
gene, which normally encodes the protein oligophrenin-1. Mutation of
this gene has been described in patients with moderate to severe
cognitive impairment. The underlying mechanisms of mental
retardation are yet to be elucidated, although recent evidence
suggests that it is associated with abnormalities in dendritic spines.
The aim of this study is to determine how oligophrenin-1 disrupts
cognitive function with perspectives to developing treatment and to
understanding normal brain function
Oligophrenin-1 is a RhoGTPase Activating Protein, which negatively
modulates RhoGTPase signalling pathways, and is implicated in
neuronal morphogenesis by regulating the actin cytoskeleton. We
have hypothesised that mutations in the OPHN-1 gene would produce
alterations in synaptic properties. We have used an OPHN-1 null
mouse model to examine the functional role of Oligophrenin-1. A first
approach was to investigate the functioning of a neuronal population
using extracellular recording. We have found that OPHN-1 null mice
displayed significantly smaller kainate-induced gamma oscillations
(20-80Hz), in CA3 area, than wild type littermates (OPHN-1-/y: 103.3
µV2 ± SE 36.9; OPHN-1+/y: 271.8 µV2 ± SE 72.7). Furthermore, we
observed a significant reduced facilitation of synaptic strength in
response to paired pulse stimulation of the mossy fibres onto CA3
neurons. We are now investigating differences in synaptic currents in
voltage-clamped CA3 pyramidal cells
58.02
Reduced inhibitory neurotransmission in the dentate gyrus of a
mouse model of mental retardation.
Powell A D, Saintot P-P, Jefferys J G R
Department of Neurophysiology, Division of Neuroscience, The Medical
School, University of Birmingham, Birmingham, B15 2TT.
Mental retardation (MR) is defined by an intelligent quotient of less than 70,
and is the most common brain disorder (prevalence 2-3%). The
mechanisms underlying MR are not fully understood; although recent
identification of putative genes responsible for MR has facilitated research.
The gene OPHN-1, which encodes for the protein Oligophrenin-1, has been
identified as malfunctioning in some mentally retarded individuals.
Oligophrenin-1 is a RhoGTPase activating protein, which negatively
modulates Rho signalling pathways. Oligophrenin-1 has been implicated in
regulating neuronal morphology, particularly at the level of the dendritic
spines.
We have examined the effect of deletion of OPHN-1 gene on the
neurophysiology of the dentate gyrus, with the prediction that OPHN-1 null
mice (OPHN1-/y) would display alterations in synaptic properties. We have
used the whole-cell voltage clamp technique to study inhibitory
neurotransmission onto granule cells in the dentate gyrus. We found that
evoked GABAergic neurotransmission is significantly smaller in OPHN-1-/y
mice (OPHN-1+/y – 908.3 ± 116.9 pA, OPHN-1-y – 381.3 ± 79.9 pA; p <
0.001). Furthermore, synaptic properties such as paired pulse and
frequency following were also significantly reduced in OPHN-1-/y neurons.
Spontaneous release events were significantly less frequent in OPHN-1-/y
neurons than in OPHN-1+/y neurons (Interevent interval - 294.5 ± 34.5 ms
and 180.7 ± 19.0 ms, respectively; p < 0.001). This reduction appeared to
be a result of less synaptic vesicles in the Readily Releasable Pool (OPHN-
1+/y - 1179 ± 270, OPHN-1-/y – 471 ± 153; p < 0.05).
58.03
Effects of clozapine withdrawal on dialysate lactate levels in two
animal models of Schizophrenia
Moran M P, De Souza I E J, Brady A T, McCabe O M, O’Shea S D,
O’Connor W T
Applied Neurotherapeutics Research Group, UCD School of
Biomolecular and Biomedical Science, UCD Conway Institute,
University College Dublin, Belfield, Dublin 4, Ireland.
Sudden discontinuation of clozapine causes rebound psychosis in
39% of patients but in only 6-11% of those taking typical
antipsychotics. The present study investigated the effect of abrupt
clozapine withdrawal on dialysate lactate levels in the mPFC of the
isolated and the maternally deprived animal models of schizophrenia.
Microdialysis was employed in the mPFC to monitor dialysate lactate
levels (µM) in vehicle and clozapine-treated (5mg/kg i.p. daily, 10
days) isolated and maternally deprived rats over a 4-day withdrawal
period. In the isolated group, young adult rats were weaned on
postnatal day 25 (P25) and individually housed while the maternally
deprived group experienced a single 24-hour period of maternal
deprivation on P9. Socially reared rats acted as controls. ANOVA was
employed for significance (n=5-8 animals per group).
Clozapine withdrawal was associated with a reducing effect on lactate
levels in the clozapine treated social control, isolated and maternally
deprived rat by -42 ±12% (p=0.0010 v’s vehicle-treated control), -28
±8% (p=0.0002 v’s vehicle treated isolated) and -45 ±8% (p=0.0001
v’s vehicle treated maternally deprived) respectively over a 4-day
withdrawal period.
The reduction in mPFC lactate in the control and in both animal
models of schizophrenia is associated with clozapine withdrawal and
may reflect a switch towards an altered glucose metabolism. Thus the
clozapine-withdrawal induced reduction in lactate mPFC levels may
play a role in rebound psychosis. The exact mechanism by which an
antipsychotic drug causes disturbances in glucose metabolism
remains to be determined.
58.04
Pharmacological manipulation of sensorimotor gating. A dual probe
microdialysis study in an animal model of schizophrenia
O’Shea S D, De Souza I E J, Brady A T, McCabe O M, Moran M P,
O’Connor W T
Applied Neurotherapeutics Research Group, UCD School of Biomolecular
and Biomedical Science, UCD Conway Institute, University College Dublin,
Belfield, Dublin 4, Ireland
The AMPA/kianate receptor antagonist CNQX (0.5mg/kg, i.p.) and the
GABAA receptor antagonist flumazenil (10mg/kg, i.p.) were combined with
dual probe microdialysis in rat medial prefrontal cortex (mPFC) and ventral
tegmental area (VTA) to compare the effects of an early postnatal stressor
(maternal deprivation) on prepulse inhibition (PPI) and basal dialysate
mPFC and VTA GABA and glutamate levels. PPI was performed on P82,
P84 and P86. Drugs were acutely administered on P84. The maternally
deprived rat experienced a 24-hour period of maternal deprivation on P9.
Socially reared rats acted as controls. Protocols were approved by UCD
Animal Research Ethics Committee and the Department of Health and
Children in accordance with European Community Directive 86/609/EC.
Basal dialysate mPFC GABA and glutamate levels were elevated by +79%
(p=0.011 v’s social control) and reduced by -93% (p