Sensory information comprises the substrate from which memories are created. Memories of spatial sensory experience are encoded by means of synaptic plasticity in the hippocampus. Hippocampal dependency on sensory information is highlighted by the fact that sudden and complete loss of a sensory modality results in an impairment of hippocampal function that persists for months. Effects are accompanied by extensive changes in the expression of neurotransmitter receptors in cortex and hippocampus, consistent with a substantial adaptive reorganization of cortical function. Whether gradual sensory loss affects hippocampal function is unclear. Progressive age-dependent hearing loss (presbycusis) is a risk factor for cognitive decline. Here, we scrutinized C57BL/6 mice that experience hereditary and cumulative deafness starting in young adulthood. We observed that 2–4 months postnatally, increases in the cortical and hippocampal expression of GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor occurred compared to control mice that lack sensory deficits. Furthermore, GABA and metabotropic glutamate receptor expression were significantly altered. Hippocampal synaptic plasticity was profoundly impaired and mice exhibited significant deficits in spatial memory. These data show that during cortical adaptation to cumulative loss of hearing, plasticity-related neurotransmitter expression is extensively altered in the cortex and hippocampus. Furthermore, cumulative sensory loss compromises hippocampal function.

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The Alzheimer disease-associated multifunctional low-density lipoprotein receptorrelated protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knockout (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The lowdensity lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic lowdensity lipoprotein receptor-related protein-1 for glutamatergic signaling in the

Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.

A hallmark of glioblastoma multiforme (GBM) is neoangiogenesis, mediated by the overexpression of vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, like bevacizumab, prolong progression-free survival in GBM, however, this treatment has been reported to be associated with a decline in neurocognitive function. Therefore, this study focused on the effects of bevacizumab on neuronal function and plasticity. We analyzed neuronal membrane properties and synaptic plasticity in rat hippocampal slices, as well as spine dynamics in dissociated hippocampal neurons, to examine the impact of bevacizumab on hippocampal function and viability. VEGF inhibition resulted in profound impairments in hippocampal synaptic plasticity as well as reductions in dendritic spine number and length. Physiological properties of hippocampal neurons were also affected. These effects of VEGF blockade on hippocampal function may play a role in compromising memory and information processing and thus, may contribute to neurocognitive dysfunction in GBM patients treated with bevacizumab.