Activity of parvalbumin-positive hippocampal interneurons is critical for network synchronization but the receptors involved therein have remained largely unknown. Here we report network and behavioral deficits in mice with selective ablation of NMDA receptors in parvalbumin-positive interneurons (NR1(PVCre-/-)). Recordings of local field potentials and unitary neuronal activity in the hippocampal CA1 area revealed altered theta oscillations (5-10 Hz) in freely behaving NR1(PVCre-/-) mice. Moreover, in contrast to controls, in NR1(PVCre-/-) mice the remaining theta rhythm was abolished by the administration of atropine. Gamma oscillations (35-85 Hz) were increased and less modulated by the concurrent theta rhythm in the mutant. Positional firing of pyramidal cells in NR1(PVCre-/-) mice was less spatially and temporally precise. Finally, NR1(PVCre-/-) mice exhibited impaired spatial working as well as spatial short- and long-term recognition memory but showed no deficits in open field exploratory activity and spatial reference learning.

CKAMP44, identified here by a proteomic approach, is a brain-specific type I transmembrane protein that associates with AMPA receptors in synaptic spines. CKAMP44 expressed in Xenopus oocytes reduced GluA1- and A2-mediated steady-state currents, but did not affect kainate- or N-methyl-D-aspartate (NMDA) receptor-mediated currents. Mouse hippocampal CA1 pyramidal neurons expressed CKAMP44 at low abundance, and overexpression of CKAMP44 led to stronger and faster AMPA receptor desensitization, slower recovery from desensitization, and a reduction in the paired-pulse ratio of AMPA currents. By contrast, dentate gyrus granule cells exhibited strong CKAMP44 expression, and CKAMP44 knockout increased the paired-pulse ratio of AMPA currents in lateral and medial perforant path-granule cell synapses. CKAMP44 thus modulates short-term plasticity at specific excitatory synapses.

Most forebrain GABAergic interneurons in rodents are born during embryonic development in the ganglionic eminences (GE) and migrate tangentially into the cortical plate. A subset, however, continues to be generated postnatally in the subventricular zone (SVZ). These interneurons populate the olfactory bulb (OB) reached via migration in the rostral migratory stream (RMS). Employing transgenic mice expressing EGFP in 5-HT 3-positive neurons, we identified additional migratory pathways in the early postnatal brain. Time-lapse imaging experiments revealed massive migration of EGFP-positive cells from the SVZ into numerous forebrain regions, including cortex, striatum, and nucleus accumbens. The neuronal fate of the migratory EGFP-labeled cells was indicated by their doublecortin (DCX) expression. Birthdating experiments, by using 5-bromo-2-deoxyuridine (BrdU) and retrovirus-based experiments, provided evidence that migrating neuroblasts were born in the SVZ postnatally and developed a distinct GABAergic phenotype. Our results demonstrate that the SVZ is a reservoir of GABAergic interneurons not only for the OB, but also for other cortical and subcortical areas.calretinin ͉ EGFP ͉ 5-HT3A receptor ͉ inhibitory interneurons ͉ neuroblast migration

Acetylcholine is a major neurotransmitter that modulates cortical functions. In addition to basal forebrain neurons that give rise to the principal cholinergic input into the cortex, a second source constituted by intrinsic cholinergic interneurons has been identified. Although these cells have been characterized anatomically, little is known about their functional role in cortical microcircuits. The paucity of this cell population has been a major hindrance for detailed electrophysiological investigations. To facilitate functional studies, we generated transgenic mice that express enhanced green fluorescent protein (

Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) form largepore nonselective channels in the plasma membrane of cells and were suggested to play a role in the pathophysiology of cerebral ischemia. To directly test a potential contribution of pannexins in ischemia-related mechanisms, we performed experiments in Px1 −/− , Px2 −/− , and Px1 −/− Px2 −/− knockout mice. IL-1β release, channel function in astrocytes, and cortical spreading depolarization were not altered in Px1 −/− Px2 −/− mice, indicating that, in contrast to previous concepts, these processes occur normally in the absence of pannexin channels. However, ischemia-induced dye release from cortical neurons was lower, indicating that channel function in Px1 −/− Px2 −/− neurons was impaired. Furthermore, Px1 −/− Px2 −/− mice had a better functional outcome and smaller infarcts than wild-type mice when subjected to ischemic stroke. In conclusion, our data demonstrate that Px1 and Px2 underlie channel function in neurons and contribute to ischemic brain damage.ATP release | gap junctions | macrophage | middle cerebral artery occlusion | metabolic inhibition

Controversy revolves around the differential contribution of NR2A- and NR2B-containing NMDA receptors, which coexist in principal forebrain neurons, to synaptic plasticity and learning in the adult brain. Here, we report genetically modified mice in which the NR2B subunit is selectively ablated in principal neurons of the entire postnatal forebrain or only the hippocampus. NR2B ablation resulted in smaller NMDA receptor-mediated EPSCs with accelerated decay kinetics, as recorded in CA1 pyramidal cells. CA3-to-CA1 field LTP remained largely unaltered, although a pairing protocol revealed decreased NMDA receptor-mediated charge transfer and reduced cellular LTP. Mice lacking NR2B in the forebrain were impaired on a range of memory tasks, presenting both spatial and nonspatial phenotypes. In contrast, hippocampus-specific NR2B ablation spared hippocampus-dependent, hidden-platform water maze performance but induced a selective, short-term, spatial working memory deficit for recently visited places. Thus, both hippocampal and extra-hippocampal NR2B containing NMDA receptors critically contribute to spatial performance.

Gating properties and surface trafficking of AMPA receptors (AMPARs) are modulated by auxiliary subunits. Here we studied the function of coexpressed auxiliary subunits belonging to two different classes. We focused on TARP γ-8 and CKAMP44 in dentate gyrus (DG) granule cells, since both subunits are highly expressed in this cell type. TARP γ-8 and CKAMP44 decrease the rate of deactivation but have an opposing influence on receptor desensitization, which accounts for their differential modulation of synaptic short-term plasticity. Furthermore, long-term plasticity (LTP) requires TARP γ-8 but not CKAMP44. The coexpression of both auxiliary subunits is necessary for the efficient targeting of AMPARs to the cell surface of DG granule cells. Finally, electrophysiological and biochemical evidence support the notion that CKAMP44 and TARP γ-8 can be contained in the same AMPAR complex.

Relay neurons in the dorsal lateral geniculate nucleus (dLGN) receive excitatory inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses are characterized by a prominent short-term depression of AMPA receptor (AMPAR)-mediated currents, but the underlying mechanisms and its function for visual integration are not known. Here we identify CKAMP44 as a crucial auxiliary subunit of AMPARs in dLGN relay neurons, where it increases AMPAR-mediated current amplitudes and modulates gating of AMPARs. Importantly, CKAMP44 is responsible for the distinctive short-term depression in retinogeniculate synapses by reducing the rate of recovery from desensitization of AMPARs. Genetic deletion of CKAMP44 strongly reduces synaptic short-term depression, which leads to increased spike probability of relay neurons when activated with high-frequency inputs from retinogeniculate synapses. Finally, in vivo recordings reveal augmented ON- and OFF-responses of dLGN neurons in CKAMP44 knockout (CKAMP44−/−) mice, demonstrating the importance of CKAMP44 for modulating synaptic short-term depression and visual input integration.