Immunization with DISC1 protein in an animal model of ADHD influences behavior and excitatory amino acids in prefrontal cortex and striatum

Abstract

The Disrupted-in-schizophrenia 1 (DISC1) gene is involved in vulnerability to neuropsychiatric disorders. Naples high-excitability (NHE) rat model neuropsychiatric problems characterized by an unbalanced mesocortical dopamine system. Here, we assessed behavioral and neurochemical effects of immunization against multimeric rat DISC1 protein in adult NHE rats, an animal model of attention-deficit hyperactivity disorder and their Random-Bred (NRB) controls. Males of both lines received subcutaneous injections of vehicle (PB), adjuvant only (AD) or recombinant rat DISC1 protein purified from E. coli, suspended in AD (anti-DISC1) at age of 30, 45 and 60 postnatal days (pnd). At 75 pnd, the rats were exposed to a Làt maze and 2 days later to an Olton eight-arm radial maze, and horizontal (HA) and vertical activities (VA) were monitored. Non-selective (NSA) and selective spatial attention (SSA) were monitored in the Làt and in the Olton maze by duration of rearings and working memory, respectively. Post mortem neurochemistry in the prefrontal cortex (PFc), dorsal (DS) and ventral (VS) striatum of L-Glutamate, L-Aspartate and L-Leucine was performed. All immunized rats showed a clear humoral IgM (but not IgG) immune response against the immunogen, indicating that immunological self-tolerance to DISC1 can be overcome by immunization. NHE rats exhibited a higher unspecific IgM response to adjuvant, indicating an immunological abnormality. The sole anti-DISC1 immunization-specific behavioral in the NHE rats was an increased horizontal activity in the Làt maze. Adjuvant treatment increased vertical activity in both lines, but in the NRB controls it increased rearing and decreased horizontal activity. Liquid chromatography/tandem mass spectrometry analysis of soluble or membrane-trapped neurotransmitters aspartate, glutamate and leucine revealed increased soluble aspartate levels in the ventral striatum of NRB controls after anti-DISC1 immunization. Immune activation by adjuvant independent of simultaneous DISC1 immunization led to other specific changes in NHE and control NRB rats. In DISC1-immunized NHE rats, horizontal activity in Lat maze correlated with membrane-trapped glutamate in PFc and in the NRB rats, duration of rearing in Olton maze correlated with membrane-trapped glutamate in PFc and aspartate in dorsal striatum. In addition to non-specific immune activation (by AD), the postnatal anti-DISC1 immune treatment led to behavioral changes related to mechanisms of activity and attention and had influenced amino acids and synaptic markers in striatum and neocortex in the adult NHE as well as control animals.

(Ascorb)ing Pb Neurotoxicity in the Developing Brain

“…Consistent with these findings, a questionnaire-and performance-based assessment of Romanian children found significant associations of ADHD-like behavior with BLL but not with other toxic metals, notably Hg and Al [83]. Interestingly, animal studies have also provided evidence for similar hyperactivity and attention deficits in rodents exposed to Pb [84][85][86][87].…”

Regional Dysregulation and Aberrant Functional Connectivity in ADHD

“…spontaneously hypertensive rats [56] or Naples High-excitability rats (Ruocco et al, 2015) [57], SNAP-25-deficient mutant coloboma mice (Baca et al, 2013) [58] or Cadherin-13, risk gene for ADHD (Rivero et al, 2015) [59]; further, Nr3c1-Bhlhb2, transcription factor silencing, axis dysregulation was involved in the development of ADHD through a disruption of prefrontal cortex functioning (Wu et al, 2016) [60]. In a pair-matching case-control study of ADHD children, it was found that Aberrant DNA methylation and histone acetylation was established in ADHD by applying the combination of p300, MYST4 and HDAC1 to obtain an accuracy of 0.9338 (Xu et al, 2015) [61].…”