Transgenic Cre-recombinase expressing mouse lines are widely used to express fluorescent proteins and opto-/chemogenetic actuators, making them a cornerstone of modern neuroscience. The investigation of interneurons in particular has benefitted from the ability to genetically target specific cell types. However, the specificity of some Cre driver lines has been called into question. Here, we show that nonspecific expression in a subset of hippocampal neurons can have substantial nonspecific functional effects in a somatostatin-Cre (SST-Cre) mouse line. Nonspecific targeting of CA3 pyramidal cells caused large optogenetically evoked excitatory currents in remote brain regions. Similar, but less severe patterns of nonspecific expression were observed in a widely used SST-IRES-Cre line, when crossed with a reporter mouse line. Viral transduction on the other hand yielded more specific expression but still resulted in nonspecific expression in a minority of pyramidal layer cells. These results suggest that a careful analysis of specificity is mandatory before the use of Cre driver lines for opto-or chemogenetic manipulation approaches.

Summary Objective Many antiseizure drugs (ASDs) act on voltage‐dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood. Methods In the present study, we determined the effects of eslicarbazepine (S‐Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham‐control and chronically epileptic pilocarpine‐treated rats. Results We found that S‐Lic causes an unexpected reduction of feed‐forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S‐Lic significantly reduced maximal firing rates in putative feed‐forward interneurons located in the CA1 stratum radiatum of sham‐control and epileptic animals. In contrast, feedback inhibition was not inhibited by S‐Lic. Instead, application of S‐Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post‐synaptic currents (IPSCs) only in epileptic and not in sham‐control animals, which persisted after washout of S‐Lic. We hypothesized that this plasticity of inhibition might rely on anti‐Hebbian potentiation of excitatory feedback inputs onto oriens‐lacunosum moleculare (OLM) interneurons, which is dependent on Ca2+‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca2+‐permeable AMPA receptors completely prevents upmodulation of feedback inhibition. Significance These results suggest that S‐Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.

Feedback inhibitory motifs are thought to be important for pattern separation across species. How feedback circuits may implement pattern separation of biologically plausible, temporally structured input in mammals is, however, poorly understood. We have quantitatively determined key properties of net feedback inhibition in the mouse dentate gyrus, a region critically involved in pattern separation. Feedback inhibition is recruited steeply with a low dynamic range (0 to 4% of active GCs), and with a non-uniform spatial profile. Additionally, net feedback inhibition shows frequency-dependent facilitation, driven by strongly facilitating mossy fiber inputs. Computational analyses show a significant contribution of the feedback circuit to pattern separation of theta modulated inputs, even within individual theta cycles. Moreover, pattern separation was selectively boosted at gamma frequencies, in particular for highly similar inputs. This effect was highly robust, suggesting that frequency dependent pattern separation is a key feature of the feedback inhibitory microcircuit.

Firing of neurons throughout the brain is determined by the precise relations between excitatory and inhibitory inputs and disruption of their balance underlies many psychiatric diseases. Whether or not these inputs covary over time or between repeated stimuli remains unclear due to the lack of experimental methods for measuring both inputs simultaneously. We developed a new analytical framework for instantaneous and simultaneous measurements of both the excitatory and inhibitory neuronal inputs during a single trial under current clamp recording. This can be achieved by injecting a current composed of two high frequency sinusoidal components followed by analytical extraction of the conductances. We demonstrate the ability of this method to measure both inputs in a single trial under realistic recording constraints and from morphologically realistic CA1 pyramidal model cells. Experimental implementation of our new method will facilitate the understanding of fundamental questions about the health and disease of the nervous system.

The firing of neurons throughout the brain is determined by the precise relations between excitatory and inhibitory inputs, and disruption of their balance underlies many psychiatric diseases. Whether or not these inputs covary over time or between repeated stimuli remains unclear due to the lack of experimental methods for measuring both inputs simultaneously. We developed a new analytical framework for instantaneous and simultaneous measurements of both the excitatory and inhibitory neuronal inputs during a single trial under current clamp recording. This can be achieved by injecting a current composed of two high frequency sinusoidal components followed by analytical extraction of the conductances. We demonstrate the ability of this method to measure both inputs in a single trial under realistic recording constraints and from morphologically realistic CA1 pyramidal model cells. Future experimental implementation of our new method will facilitate the understanding of fundamental questions about the health and disease of the nervous system.