Altered intrinsic and network properties of neocortical neurons in the Ts65Dn mouse model of Down syndrome

Abstract

All individuals with Down syndrome (DS) have a varying but significant degree of cognitive disability. Although hippocampal deficits clearly play an important role, behavioral studies also suggest that deficits within the neocortex contribute to somatosensory deficits and impaired cognition in DS. Using thalamocortical slices from the Ts65Dn mouse model of DS, we investigated the intrinsic and network properties of regular spiking neurons within layer 4 of the somatosensory cortex. In these neurons, the membrane capacitance was increased and specific membrane resistance decreased in slices from Ts65Dn mice. Examination of combined active and passive membrane properties suggests that trisomic layer 4 neurons are less excitable than those from euploid mice. The frequencies of excitatory and inhibitory spontaneous synaptic activities were also reduced in Ts65Dn neurons. With respect to network activity, spontaneous network oscillations (Up states) were shorter and less numerous in the neocortex from Ts65Dn mice when compared to euploid. Up states evoked by electrical stimulation of the ventrobasal nucleus (VBN) of the thalamus were similarly affected in Ts65Dn mice. Additionally, monosynaptic EPSCs and polysynaptic IPSCs evoked by VBN stimulation were significantly delayed in layer 4 regular spiking neurons from Ts65Dn mice. These results indicate that, in the Ts65Dn model of DS, the overall electrophysiological properties of neocortical neurons are altered leading to aberrant network activity within the neocortex. Similar changes in DS individuals may contribute to sensory and cognitive dysfunction and therefore may implicate new targets for cognitive therapies in this developmental disorder.

Outer Brain Oscillations in Down Syndrome

“…In a characterization of the intrinsic and network properties of layer 4 regular spiking pyramidal neurons in the somatosensory cortex, spontaneous excitatory and inhibitory synaptic inputs to this cell type were found to be reduced, as well as the duration of neuronal UP states -i.e., active states in the slow oscillation that alternate with silent or DOWN states at ∼1 Hz. Importantly, the authors provide results of intracellular recordings that show a decreased intrinsic excitability of the layer 4 regular spiking cells, which explains the reduced synaptic activity and the shorter duration of UP states (Cramer et al, 2015). These findings contribute to the idea that cortical network in DS may be unbalanced, or at least less excitable due to intrinsic properties of neurons, as this work shows.…”

A third copy of the Down syndrome cell adhesion molecule ( Dscam ) causes synaptic and locomotor dysfunction in Drosophila

“…Other previous studies of glutamatergic transmission in the Ts65Dn mouse model of DS have reported results that contradict our findings. They have found a reduction, and not the increase we observed, in the frequency of mEPSCs in hippocampal CA3 neurons ( Hanson et al, 2007 , Roncace et al, 2017 ), sEPSCs in neocortical neurons of Ts65Dn mice ( Cramer et al, 2015 ) and sEPSCs in neurons derived from trisomy 21 induced pluripotent stem cells ( Weick et al, 2013 ). Another study found speeding, and not the slowing we observed, of mEPSC waveform in cultured Ts65Dn hippocampal neurons ( Best et al, 2008 ).…”

“…In CA3 neurons in hippocampal slices, there is a decrease in the frequency of both miniature IPSCs (mIPSCs) and mEPSCs ( Hanson et al, 2007 , Stagni et al, 2013 ) alongside a decrease in mIPSC amplitude and no change in long term potentiation (LTP) of evoked excitatory transmission ( Hanson et al, 2007 ). Likewise, in neocortical neurons, sIPSCs and sEPSCs are less frequent but sEPSC amplitudes are reduced ( Cramer et al, 2015 ). In cerebellar slices, evoked EPSCs at parallel fibre-Purkinje cell synapses, but not at climbing fibre-Purkinje cell synapses, are slower ( Galante et al, 2009 ) or unchanged ( Das et al, 2013 ), and long-term depression (LTD) at parallel fibre-Purkinje cell synapses is unaltered ( Das et al, 2013 , Galante et al, 2009 ).…”

hsa-let-7c miRNA Regulates Synaptic and Neuronal Function in Human Neurons

“…We demonstrated that let-7c can target MECP2 (Figure 5 ), which in turn may alter intrinsic neuronal excitability as well as synapse formation (Jentarra et al, 2010 ; Marchetto et al, 2010 ; Xu et al, 2014 ). Interestingly, MeCP2 has been shown to be down regulated in T21 human neurons (Weick et al, 2013 ), a disorder that is also characterized by reductions in cellular excitability (Cramer et al, 2015 ). Given that let-7c is encoded by HSA21, it is plausible that increased expression of this miRNA could lower MeCP2 protein levels.…”