Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Reduced density of parvalbumin-expressing interneurons in CA1 caused by prenatal immune challenge.

<p><b>A</b>) Photomicrograph of the CA1 subfield of the hippocampus from pups of dams treated with poly I∶C during pregnancy (bottom) and control (top). Scale bar 200 µm, in green: somatostatin, in red: parvalbumin. <b>B</b>) and <b>C</b>) Comparison of somatostatin- (B) and parvalbumin- (C) positive cell density between the poly I∶C and the saline group, for all the CA1 subfields (total), stratum oriens (Or.) or stratum pyramidale (Pyr.) (saline n = 8, poly I∶C n = 6).</p

Prenatal immune challenge decreases the frequency and amplitude of miniIPSCs recorded in CA1 pyramidal cells.

<p><b>A</b>) Representative miniIPSC recordings from animals prenatally exposed to saline (left) or poly I∶C (right). Scale bar 500 ms (horizontal) and 60 pA (vertical). <b>B</b>) Average cumulative amplitude histogram (± SEM) of miniIPSCs recorded from the saline and poly I∶C group. Inset: average mean IPSC amplitude (100 events averaged for each cell) recorded for each group. <b>C</b>) Average cumulative inter-event interval histogram (± SEM) of miniIPSCs recorded from saline and poly I∶C treated animals. Inset: average frequency of miniIPSCs of all cells recorded for each group. <b>D</b>) Average waveform of 100 mini events from each cell for both groups (± SEM), scale 5 pA (vertical) and 5 ms (horizontal). Inset: Average miniIPSCs time constant. n = 7 for both groups.</p

Reduction of CA1 theta power in the hippocampus after prenatal immune challenge.

<p><b>A</b>) Photo of the intact hippocampal preparation with CA1 and CA3 outlined. <b>B</b>) Representative recording of spontaneous oscillatory activity in the whole hippocampal preparation <i>in vitro</i>. <b>C</b>) Average power spectrum (± SEM). Notice in both cases the peak power at around 4 Hz, corresponding to theta rhythm. <b>D</b>) The average power and peak frequency of the spontaneous self-generated theta oscillation recorded in the whole hippocampal preparation from poly I∶C- and saline-treated animals. For this experiment n = 6 in the saline and n = 7 in the poly I∶C-treated group.</p

Prenatal immune challenge reduced monosynaptic IPSCs but increased recruitment of local inhibitory feedback interneurons.

<p><b>A</b>) Recording configuration and diagram showing the two components of the mixed IPSC (composed of the monosynaptic IPSC from direct activation of local interneurons shown in red and the antidromic IPSC from feedback interneurons activated by CA1 recurrent projections shown in blue). <b>B</b>) monosynaptic IPSCs isolated by the addition of DNQX (20 µM) and AP-5 (25 µM). Left: representative recordings from both groups. Right: average monosynaptic IPSC area for both groups (n = 8 for each group). <b>C</b>) Isolation of the antidromic IPSC. Left: representative recording showing the mixed IPSC before the addition of DNQX (20 µM) and AP-5 (25 µM) and the isolated antidromic IPSC (IPSC sensitive to AP-5 and DNQX). Middle: average magnitude of the antidromic IPSC area from both groups. Right: fraction (in percent) of the mixed IPSC contributed by the antidromic IPSC (n = 8 for each group). <b>D</b>) Isolation of the NMDA receptor-dependent antidromic IPSC. Left: representative recording showing the mixed IPSC before the addition of AP-5 (25 µM) and the NMDA receptor-dependent antidromic IPSC. Middle: average magnitude of the NMDA receptor-dependent antidromic IPSC area from both groups. Right: fraction (in percent) of the mixed IPSC contributed by the NMDA receptor-dependent antidromic IPSC (n = 8 for saline and n = 7 for the poly I∶C treated group). Stimulation intensity was 300 µA and each trace displayed corresponds to the average of 5 consecutive responses.</p

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations