Developmentally altered inhibition in Ts65Dn, a mouse model of Down syndrome

We studied the development of GABA-mediated synaptic inhibition in the CA1 region of the hippocampus in Ts65Dn mice, a model system for Down syndrome (DS). While there was no significant difference in the amplitude of stimulus-evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) between acute hippocampal slices from Ts65Dn mice and diploid (2N) wild-type littermates at the end of the first and third postnatal weeks, the Ts65Dn animals showed significantly larger inhibitory responses when compared to age-matched controls at the end of the second postnatal week. This transient change in evoked inhibition was strikingly layer specific, observed only when stimulating in the strata radiatum and pyramidale but not in the stratum oriens. In addition, the frequency (but not amplitude) of spontaneous action potential independent miniature inhibitory postsynaptic currents (mIPSCs) was significantly increased in the Ts65Dn mice during the second postnatal week. Additional measurements of paired-pulse ratios showed no significant difference between the genotypes. We conclude that the excess inhibition at the end of the second postnatal week in Ts65Dn mice is not due to increases in release probability or postsynaptic quantal size. Overall these experiments indicate that there is a specific disruption of the normal developmental progression of inhibitory synaptic transmission in Ts65Dn mice at a critical time point in the development of neuronal circuitry. This raises the possibility that a transient early disruption of inhibitory function may have lasting impact on other network properties and could contribute to later neural circuit dysfunction in DS.