Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function

Abstract

Schizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive function in both sexes. Pregnant mice were injected with 26mg/kg(i.p.) of Methylazoxy-methanol acetate (MAM) or saline (5ml/kg) on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Behavioral, histological and electrophysiological and mass spectrometry-based comparative proteomic techniques were employed to assess the schizotypic-like characteristics and cognitive function of adult male and female offspring (MAM-or saline-treated). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute administration of the NMDA receptor antagonist, MK-801, compared to saline treated mice. Male MAM-16, but not MAM-17 treated mice showed decreased pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited reduced hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory, while only male MAM-16 treated mice exhibited deficits in the delayed alternation task. The neurophysiological mechanisms that underlie these cognitive functions were further investigated. Both male and female MAM-16 treated mice had significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses, while only male MAM-16 treated mice exhibited decreased LTP in the PFC. Proteomic analyses of PFC lysates further showed significant MAM-and sex-dependent differences in regulation . CC-BY-NC-ND 4.

Effect of Neonatal Treatment With the NMDA Receptor Antagonist, MK-801, During Different Temporal Windows of Postnatal Period in Adult Prefrontal Cortical and Hippocampal Function

“…The neurodevelopmental MAM16 mouse model of SZ revealed sex differences in PFC-dependent cognitive function, PFC proteome, and PV expression in the PFC and the HPC (Chalkiadaki et al, 2019). Moreover, prenatal PolyI: C treatment led to PPI sex-specific deficits (O'Leary et al, 2014;Ratnayake et al, 2014), to male-specific impairments in fear conditioning (Vorhees et al, 2012), in set-shifting task (Zhang et al, 2012), and in recognition memory test (Howland et al, 2012) as well as to female-specific dysfunction in spatial memory (O'Leary et al, 2014).…”

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

“…Patients with psychosis display hyper-sensitivity to psychomotor stimulants which can be modeled in rats by measuring locomotor activity before and after administration of the NMDA antagonist, MK-801 10,41,43 . Consistent with previous literature 44 , stress/vehicle rats showed an increase in locomotor activity at baseline, compared to control/vehicle rats ( Fig.…”

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

“…In the prenatal immune challenge model of SZ in mice, for example, distinct sex differences were found in microglial distribution, process arborization, oxidative stress, synaptic function, and expression of inflammatory genes that may be relevant to the increased incidence of severe SZ in males [ 48 ]. In the MAM model of SZ in mice, sex differences have been reported not only in neuronal activity, but also in the expression of regulatory proteins, primarily those involved in glutamatergic signaling in the prefrontal cortex [ 49 ]. While glutamatergic transmission drives excitation in cortical circuits, inhibition from gamma aminobutyric acid (GABA)ergic interneurons plays a key role in regulating excitability of pyramidal neurons in order to generate synchronized firing patterns required for efficient communication between neuronal ensembles [ 11 ].…”

“…For example, a decrease in parvalbumin-positive interneurons, in line with those observed in human SZ patients, in both MAM-treated male and female rats has been shown [ 10 , 52 ]. Conversely, Chalkiadaki et al [ 49 ] found that MAM exposure decreased the expression of parvalbumin in male but not in female mice, and that only male mice exhibited prefrontal cortical deficits in activity, a discrepancy that may be explained by the different species employed.…”