Victor Sabanov

Proper synaptic vesicle formation and neuronal network activity critically rely on syndapin I.

Synaptic transmission relies on effective and accurate compensatory endocytosis. F‐BAR proteins may serve as membrane curvature sensors and/or inducers and thereby support membrane remodelling processes; yet, their in vivo functions urgently await disclosure. We demonstrate that the F‐BAR protein syndapin I is crucial for proper brain function. Syndapin I knockout (KO) mice suffer from seizures, a phenotype consistent with excessive hippocampal network activity. Loss of syndapin I causes defects in presynaptic membrane trafficking processes, which are especially evident under high‐capacity retrieval conditions, accumulation of endocytic intermediates, loss of synaptic vesicle (SV) size control, impaired activity‐dependent SV retrieval and defective synaptic activity. Detailed molecular analyses demonstrate that syndapin I plays an important role in the recruitment of all dynamin isoforms, central players in vesicle fission reactions, to the membrane. Consistently, syndapin I KO mice share phenotypes with dynamin I KO mice, whereas their seizure phenotype is very reminiscent of fitful mice expressing a mutant dynamin. Thus, syndapin I acts as pivotal membrane anchoring factor for dynamins during regeneration of SVs.

Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

&NA; Many clinical and molecular features of the fragile X syndrome, a common form of intellectual disability and autism, can be modeled by deletion of the Fmr1 protein (Fmrp) in mice. Previous studies showed a decreased expression of several components of the GABAergic system in Fmr1 knockout mice. Here, we used this mouse model to investigate the functional consequences of Fmrp deletion on hippocampal GABAergic inhibition in the CA1‐region of the hippocampus. Whole‐cell patch‐clamp recordings demonstrated a significantly reduced amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and a decrease in the amplitude and frequency of spontaneous IPSCs. In addition, miniature IPSCs were reduced in amplitude and frequency and decayed significantly slower than mIPSCs in controls. Quantitative real‐time PCR revealed a significantly lower expression of &agr;2, &bgr;1 and &dgr; GABAA receptor subunits in the hippocampus of the juvenile mice (P22) compared to wild‐type littermates. Correspondingly, we found also at the protein level reduced amounts of &agr;2, &bgr;1 and &dgr; subunits in Fmr1 knockout mice. Overall, these results demonstrate that the reduction in several components of the GABAergic system is already present at young age and that this reduction results in measurable abnormalities on GABAA receptor‐mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model. HighlightsThe expression of &agr;2, &bgr;1 and &dgr; GABAA receptor subunit mRNA is significantly decreased in young mice.The expression of GABAA &agr;2, &bgr;1 and &dgr; subunits is significantly reduced at the protein level.Evoked, spontaneous and miniature IPSCs in CA1 pyramidal neurons are reduced.GABAergic dysfunction contributes to behavioral and cognitive deficits of Fmr1 mice.

Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation

BACKGROUND Neuroplastin cell recognition molecules have been implicated in synaptic plasticity. Polymorphisms in the regulatory region of the human neuroplastin gene (NPTN) are correlated with cortical thickness and intellectual abilities in adolescents and in individuals with schizophrenia. METHODS We characterized behavioral and functional changes in inducible conditional neuroplastin-deficient mice. RESULTS We demonstrate that neuroplastins are required for associative learning in conditioning paradigms, e.g., two-way active avoidance and fear conditioning. Retrograde amnesia of learned associative memories is elicited by inducible neuron-specific ablation of Nptn gene expression in adult mice, which shows that neuroplastins are indispensable for the availability of previously acquired associative memories. Using single-photon emission computed tomography imaging in awake mice, we identified brain structures activated during memory recall. Constitutive neuroplastin deficiency or Nptn gene ablation in adult mice causes substantial electrophysiologic deficits such as reduced long-term potentiation. In addition, neuroplastin-deficient mice reveal profound physiologic and behavioral deficits, some of which are related to depression and schizophrenia, which illustrate neuroplastins essential functions. CONCLUSIONS Neuroplastins are essential for learning and memory. Retrograde amnesia after an associative learning task can be induced by ablation of the neuroplastin gene. The inducible neuroplastin-deficient mouse model provides a new and unique means to analyze the molecular and cellular mechanisms underlying retrograde amnesia and memory.

TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons

TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca2+-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-d-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4−/− neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4−/− neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication.

Distinct Properties of Long-Term Potentiation in the Dentate Gyrus along the Dorsoventral Axis: Influence of Age and Inhibition

The hippocampus is important for spatial navigation, episodic memory and affective behaviour. Increasing evidence suggests that these multiple functions are accomplished by different segments along the dorsal-ventral (septal-temporal) axis. Long-term potentiation (LTP), the best-investigated cellular correlate of learning and memory, has distinct properties along this axis in the CA1 region, but so far, little is known about longitudinal differences in dentate gyrus (DG). Therefore, here we examined potential dorsoventral differences in DG-LTP using in vitro multi-electrode array recordings. In young mice, we found higher basal synaptic transmission in the dorsal DG, while the LTP magnitude markedly increased towards the ventral pole. Strikingly, these differences were greatly reduced in slices from middle-aged mice. Short-term plasticity, evaluated by paired-pulse ratios, was similar across groups. Recordings in the presence and absence of GABAA-receptor blocker picrotoxin suggested a higher inhibitory tone in the ventral DG of young mice, confirmed by an increased frequency of miniature inhibitory postsynaptic currents. Our findings support the view that the hippocampus contains discrete functional domains along its dorsoventral axis and demonstrate that these are subject to age-dependent changes. Since these characteristics are presumably conserved in the human hippocampus, our findings have important clinical implications for hippocampus- and age-related disorders.

Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling

Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.02196.001

Transient and localized optogenetic activation of somatostatin-interneurons in mouse visual cortex abolishes long-term cortical plasticity due to vision loss.

Unilateral vision loss through monocular enucleation (ME) results in partial reallocation of visual cortical territory to another sense in adult mice. The functional recovery of the visual cortex occurs through a combination of spared-eye potentiation and cross-modal reactivation driven by whisker-related, somatosensory inputs. Brain region-specific intracortical inhibition was recently recognized as a crucial regulator of the cross-modal component, yet the contribution of specific inhibitory neuron subpopulations remains poorly understood. Somatostatin (SST)-interneurons are ideally located within the cortical circuit to modulate sensory integration. Here we demonstrate that optogenetic stimulation of visual cortex SST-interneurons prior to eye removal decreases ME-induced cross-modal recovery at the stimulation site. Our results suggest that SST-interneurons act as local hubs, which are able to control the influx and extent of cortical cross-modal inputs into the deprived cortex. These insights critically expand our understanding of SST-interneuron-specific regulation of cortical plasticity induced by sensory loss.