Comparing Mouse and Rat Hippocampal Place Cell Activities and Firing Sequences in the Same Environments.

Hippocampal place cells are key to spatial representation and spatial memory processing. They fire at specific locations in a space (place fields) and fire in precise patterns during theta sequences and during ripple-associated replay events. These phenomena have been extensively studied in rats, but to a less extent in mice. The availability of versatile genetic manipulations gives mice an advantage for place cell studies. However, it is unknown how place fields and place cell sequences in the same environment differ between mice and rats. Here, we provide a quantitative comparison in place field properties, as well as theta sequences and replays, between rats and mice as they ran on the same novel track and as they rested afterwards. We found that place cells in mice display less spatial specificity with more but smaller place fields. Theta oscillations, theta phase precession and aspects of theta sequences in mice are similar as those in rats. The ripple-associated replay, however, is relatively rare during stopping on the novel track in mice. The replay is present during resting after the track running, but is weaker in mice than the replay in rats. Our results suggest that place cells in mice and rats are qualitatively similar, but with substantial quantitative differences.

Impaired spatial memory codes in a mouse model of Rett syndrome.

The Mecp2+/- mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivo in RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is accompanied by an enhanced baseline firing synchrony of place cells within ripple oscillations during rest, which consequently occludes the increase in synchrony after a novel experience. Behaviorally, contextual memory is normal at short but not long time scale in RTT mice. Our results suggest that hypersynchrony interferes with memory consolidation and leads to impaired spatial memory codes in RTT mice, providing a possible circuit mechanism for memory deficits in Rett Syndrome.

Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model.

Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.

Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.

We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.