GABAergic Synapse Properties May Explain Genetic Variation in Hippocampal Network Oscillations in Mice

Cognitive ability and the properties of brain oscillation are highly heritable in humans. Genetic variation underlying oscillatory activity might give rise to differences in cognition and behavior. How genetic diversity translates into altered properties of oscillations and synchronization of neuronal activity is unknown. To address this issue, we investigated cellular and synaptic mechanisms of hippocampal fast network oscillations in eight genetically distinct inbred mouse strains. The frequency of carbachol-induced oscillations differed substantially between mouse strains. Since GABAergic inhibition sets oscillation frequency, we studied the properties of inhibitory synaptic inputs (IPSCs) received by CA3 and CA1 pyramidal cells of three mouse strains that showed the highest, lowest and intermediate frequencies of oscillations. In CA3 pyramidal cells, the frequency of rhythmic IPSC input showed the same strain differences as the frequency of field oscillations. Furthermore, IPSC decay times in both CA1 and CA3 pyramidal cells were faster in mouse strains with higher oscillation frequencies than in mouse strains with lower oscillation frequency, suggesting that differences in GABAA-receptor subunit composition exist between these strains. Indeed, gene expression of GABAA-receptor β2 (Gabrb2) and β3 (Gabrb2) subunits was higher in mouse strains with faster decay kinetics compared with mouse strains with slower decay kinetics. Hippocampal pyramidal neurons in mouse strains with higher oscillation frequencies and faster decay kinetics fired action potential at higher frequencies. These data indicate that differences in genetic background may result in different GABAA-receptor subunit expression, which affects the rhythm of pyramidal neuron firing and fast network activity through GABA synapse kinetics

Novel Candidate Genes Associated with Hippocampal Oscillations

The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD recombinant inbred mouse strains. Spontaneous activity and carbachol-induced fast network oscillations were analyzed with spectral and cross-correlation methods and the resulting traits were used for mapping quantitative trait loci (QTLs), i.e., regions on the genome that may influence hippocampal function. Using genome-wide hippocampal gene expression data, we narrowed the QTLs to eight candidate genes, including Plcb1, a phospholipase that is known to influence hippocampal oscillations. We also identified two genes coding for calcium channels, Cacna1b and Cacna1e, which mediate presynaptic transmitter release and have not been shown to regulate hippocampal network activity previously. Furthermore, we showed that the amplitude of the hippocampal oscillations is genetically correlated with hippocampal volume and several measures of novel environment exploration

Distributed Network Actions by Nicotine Increase the Threshold for Spike-Timing-Dependent Plasticity in Prefrontal Cortex

SummaryNicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABAA receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP

Waarde van wetenschap:Observeren, weten en meten

Het is belangrijk en urgent dat de planbureaus de effecten van investeringen in wetenschap systematisch gaan evalueren met een ander instrumentarium. De huidige modelmatige aanpak is daarvoor ongeschikt. De waarde van investeringen in wetenschap wordt daardoor nu niet systematisch meegenomen bij beleidsevaluaties of het evalueren van partijprogramma’s. Hierdoor wordt investeren in wetenschap onterecht als een kostenpost gezien

Waarde van wetenschap:Observeren, weten en meten

Het is belangrijk en urgent dat de planbureaus de effecten van investeringen in wetenschap systematisch gaan evalueren met een ander instrumentarium. De huidige modelmatige aanpak is daarvoor ongeschikt. De waarde van investeringen in wetenschap wordt daardoor nu niet systematisch meegenomen bij beleidsevaluaties of het evalueren van partijprogramma’s. Hierdoor wordt investeren in wetenschap onterecht als een kostenpost gezien

Influence of the decay time of the GABAergic postsynaptic current on the spatial spread of network activity

The subunit composition of the GABAA receptor determines the decay time of the GABAergic inhibitory postsynaptic current (IPSC). In mice in which the α1 subunit is deleted, the decay time is longer than in wild-type mice, while the spatial spread of activity in the visual cortex following local stimulation is reduced. Using a simple network model of the visual cortex, we show that this reduced spread of activity could be accounted for by the longer IPSC decay time. After local stimulation of the network, a patch of activity develops, the equilibrium size of which depends on the IPSC decay time

Role of synaptic inhibition in spatiotemporal patterning of cortical activity

Developmental upregulation of the GABAA receptor α1 subunit causes a faster decay of GABAergic inhibitory postsynaptic currents (IPSCs) in the visual cortex around the time of eye opening. In α1 deficient mice, a juvenile type of GABAA receptors is retained during maturation. As a result the decay time of the IPSCs is longer in α1-/- mice than in WT mice during the whole life span of the mice. Hence they form a valuable mouse model for studies on cellular aspects of neuronal network functioning. Using voltage sensitive dye imaging methods, we monitored the spatiotemporal excitation patterning in visual cortex slices upon local stimulation of the network. We found that in the α1-/- mice, the ability of the network to fire synchronously at γ-frequencies (20-50Hz) is diminished. This finding indicates that early onset of GABA synapse maturation is required for the normal neuronal network function in the maturating visual cortex

Mice lacking the major adult GABAA receptor subtype have normal number of synapses, but retain juvenile IPSC kinetics until adulthood

There is a large variation in structurally and functionally different GABAA receptor subtypes. The expression pattern of GABAA receptor subunits is highly regulated, both temporarily and spatially. Especially during development, profound changes in subunit expression have been described. In most brain areas, the GABAA receptor α1 subunit replaces the α2 and/or α3 subunit as major α1 subunit. This is accompanied by a marked decrease in the open time of GABAA receptors and hence in the duration of postsynaptic responses. We describe here the development of GABAergic, synaptic transmission in mice lacking the α1 subunit. We show that α1 is to a large extent-but not entirely-responsible for the relatively short duration of postsynaptic responses in the developing and the mature brain. However, α1 already affects GABAergic transmission in the neonatal cerebral cortex when it is only sparsely expressed. It appears that the α1 -/- mice do not show a large reduction in GABAergic synapses but do retain long-lasting postsynaptic currents into adulthood. Hence, they form a good model to study the functional role of developmental GABAA receptor subunit switching