Minocycline and Risperidone Prevent Microglia Activation and Rescue Behavioral Deficits Induced by Neonatal Intrahippocampal Injection of Lipopolysaccharide in Rats

Abstract

BackgroundVarious signs of activation of microglia have been reported in schizophrenia, and it is hypothesized that microglia activation is closely associated with the neuropathology of schizophrenia.MethodsNeonatal intrahippocampal injection of lipopolysaccharide (LPS), an activator of microglia, was performed in rats at postnatal day 7 (P7), and they were separately given saline, risperidone (0.5 mg/kg), minocycline (40 mg/kg) or a combination of both of them at P42 for consecutive 14 days. Behavioral changes (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were examined and the number of microglia was assessed by using immunohistochemistry in adulthood.ResultsThe adult rats in LPS-injected group showed obvious behavioral alteration (e. g. deficits in social interaction, novel object recognition and prepulse inhibition) and a dramatic increase of number of activated microglial cells in the hippocampus and other brain regions such as cerebral cortex and thalamus compared to those in saline-injected group. Interestingly, application of either minocycline, risperidone or both of them significantly rescued behavioral deficits and attenuated microglia activation.ConclusionOur results suggest that inhibition of microglia activation may be one of mechanisms underlying the antipsychotic effect of minocycline and risperidone.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Other in utero or neonatal neurotoxic manipulations also produce PPI deficits in adult rats, including methylazoxymethanol (MAM) exposure (Le Pen et al 2006), elevated neonatal allopregnanolone (Darbra et al 2014), and neonatal administration of NMDA antagonists (Uehara et al 2010). In some cases, the expression of PPI deficits induced by these early developmental manipulations can be blocked by acute treatments during adulthood, using antipsychotics (e.g., clozapine: Ribeiro et al 2013), putative neuroprotective agents (e.g., minocycline: Zhu et al 2014b), and glycinergic agents (Le Pen et al 2003). Thus, it appears that PPI deficits are a common adult behavioral response to a wide range of perturbations in early rodent brain development, and particularly those that impact the mesial temporal lobe by various mechanisms.…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…in adulthood (Llorente-Berzal et al 2012); however risperidone treatment in adolescence (0.5 mg/kg from PND42 to PND56) did not affect NOR at PND 60, i.e. after 4 drug-free days (Zhu et al 2014). …”

“…At PND65, following treatment with this APD, no significant change in Iba-1 labelled activated microglia was observed in the cerebral cortex, the hippocampus and the thalamus of risperidone-treated rats (Zhu et al 2014). …”

“…Social interaction responses in adulthood were normal after chronic adolescent treatment with typical APD haloperidol (Gao and Li 2014) and atypical APDs such as risperidone (Zhu et al 2014) or olanzapine and aripiprazole (De Santis et al 2016) regardless of the route of administration.…”

“…However, a recent preclinical study has suggested that chronic APD treatment per se can alter immune responses, by demonstrating increased density and amoeboid reactive morphology of activated microglia in brain regions such as hippocampus, striatum and anterior cingulate cortex after chronic treatment with haloperidol and olanzapine in adult naïve rats (Cotel et al 2015). By contrast, an earlier study did not find any significant change in activated microglia with chronic risperidone treatment in adolescent rats (Zhu et al 2014). Therefore, it remains unanswered how APDs exert their immunoregulatory effects and whether the underlying neuropathological status can determine APDs' action on the immune response.…”