Hippocampal modulation of sensorimotor processes

Bast, Tobias; Feldon, Joram

doi:10.1016/s0301-0082(03)00112-6

Cited by 241 publications

(176 citation statements)

References 233 publications

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“…The adult emergence of poly(I:C)--induced PPI deficit is consistent with numerous previous studies in mice (e.g., Lipina et al, 2013;Pacheco--López et al, 2013;Vuillermot et al, 2010) and rats ; but see also Wolff and Bilkey, 2010). Since the hippocampal formation is one of several neuronal substrates modulating sensorimotor gating (Bast and Feldon, 2003), deficient hippocampal expression of presynaptic proteins may readily contribute to the attenuation of PPI in immune--challenged offspring. Even though this hypothesis warrants further examination, it would be consistent with other environmental stress models…”

supporting

confidence: 90%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

126

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Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre-and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. AbstractPrenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre--and postsynaptic deficits.Using a well--established mouse model of maternal exposure to the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)--exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early--life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial a...

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supporting

confidence: 90%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

126

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“…Alternatively, given the dissociation we observe in the effects of environmental enrichment, it is of significant interest that learning and memory are particularly susceptible to dorsal hippocampal manipulations, 42,43 while locomotor activity and PPI, which are modulated, but not mediated, by the hippocampus (in that its involvement is not critical to performance of the behavior), have been shown to be much more susceptible to ventral hippocampal lesions. 44 Environmental enrichment may be regionally specific, providing another potential explanation for the discrepancy in the enrichment effect; however, further experiments would be required in order to resolve this question.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

et al. 2007

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Phospholipase C-b1 (PLC-b1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-b1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-b1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenialike symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-b1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.

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“…Moreover, regional disinhibition, by causing aberrant drive of projections, may disrupt neural activity and cognitive processing in distal sites. Consistent with distal effects, rodent studies show that hippocampal disinhibition and overactivity cause dopamine system upregulation and associated behavioral effects (including locomotor hyperactivity) Bast and Feldon 2003;Lodge and Grace 2011;Gilani et al 2014), which -given the strong link between dopamine and psychosis (Howes and Kapur 2009) explain the consistent correlation of hippocampal overactivity and psychosis in schizophrenia (Liddle et al 1992;Schobel et al 2009;Heckers and Konradi 2014). Considering local and distal effects, we hypothesized that hippocampal neural disinhibition impairs hippocampus-dependent memory and, based on strong hippocampo-prefrontal connectivity, also prefrontal-dependent cognitive function, including attention (Bast 2011).…”

Section: Introductionmentioning

confidence: 87%

“…The task resembles the everyday problem of remembering new places and routes, and similar human tests using virtual or real-space analogues of the watermaze reveal marked deficits in schizophrenia and age-related cognitive decline (Hort et al 2007;Fajnerova et al . For comparison and to identify behaviorally effective doses without gross sensorimotor effects, we first examined effects on locomotor activity and startle prepulse inhibition (PPI), with locomotor hyperactivity and PPI disruption also being widely-used psychosis-related indices (Bast and Feldon 2003;Swerdlow et al 2008). To examine neural changes caused by hippocampal GABA dysfunction, we conducted in vivo electrophysiological recordings in the vicinity of the infusion site .…”

Section: Introductionmentioning

confidence: 99%