The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome

Abstract

Down's syndrome (DS) is the most common cause of mental retardation, and memory impairments are more severe in DS than in most if not all other causes of mental retardation. The Ts65Dn mouse, a genetic model of DS, exhibits phenotypes of DS, including memory impairments indicative of hippocampal dysfunction. We examined functional synaptic connectivity in area CA3 of the hippocampus of Ts65Dn mice using organotypic slice cultures as a model. We found reductions in multiple measures of synaptic function in both excitatory and inhibitory inputs to pyramidal neurons in CA3 of the Ts65Dn hippocampus. However, associational synaptic connections between pyramidal neurons were more abundant and more likely to be active rather than silent in the Ts65Dn hippocampus. Synaptic potentiation was normal in these associational connections. Decreased overall functional synaptic input onto pyramidal neurons expressed along with the specific hyperconnectivity of associational connections between pyramidal neurons will result in predictable alterations of CA3 network function, which may contribute to the memory impairments seen in DS.

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

“…In addition, the imperfect association of ACh markers with behavior may also reflect independent consequences of age in the partial trisomy mice, for example in other neurotransmitters (Fernandez et al, 2007) or neurobiological processes. These other processes include impaired long-term potentiation (Costa and Grybko, 2005;Fernandez et al, 2007;Kleschevnikov et al, 2004;Siarey et al, 1997), enhanced long-term depression (Siarey et al, 1999), impaired expression of brainderived neurotrophic factor (Seo and Isacson, 2005), altered signaling pathways (Siarey et al, 2006), and altered neuroanatomical organization of the hippocampus Hanson et al, 2007;Kurt et al, 2004;Lorenzi and Reeves, 2006).…”

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

“…Despite an overabundance of active synaptic connections between pyramidal neurons in the Ts65Dn CA3 region as compared to WT this study demonstrated a general decrease in the function of the Ts65Dn excitatory and inhibitory synaptic inputs. (22).…”

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

“…All neuron pairs not showing a functional connection were tested by pairing 1 Hz presynaptic with depolarization of the postsynaptic neuron to 0 mV. In contrast to work in different mouse strains (Hanson et al, 2007), silent synapses (synapses without initial responses at Ϫ70 mV, but which could be awakened by this stimuli) were very infrequently observed (ϳ5% occurrence). Because the occurrence was too low, this class of synapse could not be independently analyzed.…”