Proceedings of The Physiological Society

Physiology 2012 (Edinburgh) (2012) Proc Physiol Soc 27, C64

Oral Communications

Divergent circuit changes partially re-balance cortical layer IV thalamocortical responses in a mouse model of Fragile X syndrome

A. Domanski1,2, J. T. Isaac2,3, P. C. Kind1

1. University of Edinburgh, Edinburgh, Midlothian, United Kingdom. 2. NINDS, National Institues of Health, Bethesda, Maryland, United States. 3. Eli Lilly and Company, Erl Wood, United Kingdom.

Fragile X Syndrome (FXS) is the most common heritable form of intellectual disability and autism. It is caused by a single gene mutation and symptoms include cognitive impairment, seizures, deficits in sensory gating and abnormal sleep. Dissecting the pathophysiology of sensory cortical activity helps explain sensory phenotypes in FXS and offers insights into higher cognitive dysfunction. Studies in the Fmr1-KO mouse model of FXS show developmental abnormalities in cortical neuronal physiology. In particular, altered plasticity at the thalamocortical (TC) synapse was shown in somatosensory cortex during postnatal days 6-12 (P6-12)(1). Between these ages TC responses undergo coordinated developmental maturation in wild-type (WT) mice. (2,3). Appearance of local feed-forward inhibition (FFI), modulation of cell intrinsic properties and synaptic kinetics sharpen the temporal resolution of cortical TC responses by controlling synaptic integration in cortical layer IV (LIV) excitatory neurons. We sought to examine these processes in juvenile Fmr1-KO mice. Intrinsic membrane and synaptic properties of Fmr1-KO (P10-11) excitatory neurons were investigated using electrophysiology in a TC slice preparation (4). LIV excitatory neurons (WT: n=33, KO: n=37) displayed increased input resistance with unaltered whole-cell capacitance. Effective membrane time constant, τm was therefore longer (KO: 55±3 vs. WT: 39±4ms, P<0.002). Values are mean±S.E.M., compared by t-test. Electrical stimulation in ventrobasal thalamus evoked feed-forward EPSP-IPSP sequences in excitatory neurons (WT: n=30, KO: n=31). Strength of FFI was quantified as IPSC/EPSC peak ratio (I/E). TC FFI was enhanced in Fmr1-KOs (I/E ratio, KO: 5.0±0.5 vs. WT: 3.9±0.5 P<0.05, Mann-Whitney test). Latency and kinetics of FFI EPSC-IPSCs were additionally prolonged. Furthermore, repetitive TC stimulation at behaviorally relevant frequencies (5-50Hz) induced exaggerated short-term depression (STD) of both EPSCs and IPSCs in Fmr1-KOs. We used a conductance-based ball-and-stick model with depressing TC and FFI inputs to investigate interaction of these phenotypes on the temporal integration window at TC synapses. At WT FFI ranges (I/E<3), longer τm dominated and a broad temporal integration window was observed in the Fmr1-KO model across a range of input frequencies. Increasing FFI to ranges recorded in Fmr1-KOs (3<I/E<10) stabilised and then further sharpened the integration window relative to matched WT simulations. Individual rescue in silico of τm, synaptic kinetics or STD to WT levels could not return improve TC function and exacerbated temporal resolution defects. These data support the conclusion that multiple divergent circuit alterations, including stronger feed-forward inhibitory drive interact in juvenile Fmr1-KOs to partially re-tune TC temporal discrimination.

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