A comparison of striatal-dependent behaviors in wild-type and hemizygous Drd1a and Drd2 BAC transgenic mice.

Studies of striatal physiology and motor control have increasingly relied on the use of bacterial artificial chromosome (BAC) transgenic mice expressing fluorophores or other genes under the control of genetic regulatory elements for the dopamine D1 receptor (D1R) or dopamine D2 receptor (D2R). Three recent studies have compared wild-type, D1R, and D2R BAC transgenic mice, and found significant differences in physiology and behavior, calling into question the use of these mice in studies of normal circuit function. We repeated the behavioral portions of these studies in wild-type C57BL/6 mice and hemizygous Drd1a-td Tomato (D1-Tmt), Drd1a-eGFP (D1-GFP), and Drd2-eGFP (D2-GFP) mice backcrossed into the C57BL/6 background. Our three laboratories independently found that open-field locomotion, acute locomotor responses to cocaine (20 mg/kg), locomotor sensitization to 5 d of daily injections of cocaine (15 mg/kg) or amphetamine (3 mg/kg), cocaine (20 mg/kg) conditioned place preference, and active avoidance learning to paired light and footshock were indistinguishable in these four mouse lines. These results suggest that while it is crucial to screen new transgenic mouse lines for abnormal behavior and physiology, these BAC transgenic mouse lines remain extremely valuable tools for evaluating the cellular, synaptic, and circuit basis of striatal motor control and associative learning.

Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.

Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.

Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine.

In Parkinson's disease (PD), dopamine depletion alters neuronal activity in the direct and indirect pathways and leads to increased synchrony in the basal ganglia network. However, the origins of these changes remain elusive. Because GABAergic interneurons regulate activity of projection neurons and promote neuronal synchrony, we recorded from pairs of striatal fast-spiking (FS) interneurons and direct- or indirect-pathway MSNs after dopamine depletion with 6-OHDA. Synaptic properties of FS-MSN connections remained similar, yet within 3 days of dopamine depletion, individual FS cells doubled their connectivity to indirect-pathway MSNs, whereas connections to direct-pathway MSNs remained unchanged. A model of the striatal microcircuit revealed that such increases in FS innervation were effective at enhancing synchrony within targeted cell populations. These data suggest that after dopamine depletion, rapid target-specific microcircuit organization in the striatum may lead to increased synchrony of indirect-pathway MSNs that contributes to pathological network oscillations and motor symptoms of PD.

Asymmetric temporal integration of layer 4 and layer 2/3 inputs in visual cortex.

Neocortical neurons in vivo receive concurrent synaptic inputs from multiple sources, including feedforward, horizontal, and feedback pathways. Layer 2/3 of the visual cortex receives feedforward input from layer 4 and horizontal input from layer 2/3. Firing of the pyramidal neurons, which carries the output to higher cortical areas, depends critically on the interaction of these pathways. Here we examined synaptic integration of inputs from layer 4 and layer 2/3 in rat visual cortical slices. We found that the integration is sublinear and temporally asymmetric, with larger responses if layer 2/3 input preceded layer 4 input. The sublinearity depended on inhibition, and the asymmetry was largely attributable to the difference between the two inhibitory inputs. Interestingly, the asymmetric integration was specific to pyramidal neurons, and it strongly affected their spiking output. Thus via cortical inhibition, the temporal order of activation of layer 2/3 and layer 4 pathways can exert powerful control of cortical output during visual processing.

Dendritic synapse location and neocortical spike-timing-dependent plasticity.

While it has been appreciated for decades that synapse location in the dendritic tree has a powerful influence on signal processing in neurons, the role of dendritic synapse location on the induction of long-term synaptic plasticity has only recently been explored. Here, we review recent work revealing how learning rules for spike-timing-dependent plasticity (STDP) in cortical neurons vary with the spatial location of synaptic input. A common principle appears to be that proximal synapses show conventional STDP, whereas distal inputs undergo plasticity according to novel learning rules. One crucial factor determining location-dependent STDP is the backpropagating action potential, which tends to decrease in amplitude and increase in width as it propagates into the dendritic tree of cortical neurons. We discuss additional location-dependent mechanisms as well as the functional implications of heterogeneous learning rules at different dendritic locations for the organization of synaptic inputs.