Elimination of the Vesicular Acetylcholine Transporter in the Forebrain Causes Hyperactivity and Deficits in Spatial Memory and Long-Term Potentiation.

Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation.

Filed under: Depression Treatment

Proc Natl Acad Sci U S A. 2012 Oct 8;
Martyn AC, De Jaeger X, Magalhães AC, Kesarwani R, Gonçalves DF, Raulic S, Guzman MS, Jackson MF, Izquierdo I, Macdonald JF, Prado MA, Prado VF

Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.
HubMed – depression

Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat.

Filed under: Depression Treatment

Proc Natl Acad Sci U S A. 2012 Oct 8;
Bagot RC, Zhang TY, Wen X, Nguyen TT, Nguyen HB, Diorio J, Wong TP, Meaney MJ

Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the Grm1 gene in the rat as a function of maternal care. Grm1 encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.e., high-LG mothers) that was associated with a decrease in the methylation of Grm1. ChIP assays showed increased levels of histone 3 lysine 9 acetylation and histone 3 lysine 4 trimethylation of Grm1 in hippocampus from the adult offspring of high-LG compared with low-LG mothers. These histone posttranslational modifications were highly correlated, and both associate inversely with DNA methylation and positively with transcription. Studies of mGluR1 function showed increased hippocampal mGluR1-induced long-term depression in the adult offspring of high-LG compared with low-LG mothers, as well as increased paired-pulse depression (PPD). PPD is an inhibitory feedback mechanism that prevents excessive glutamate release during high-frequency stimulation. The maternal effects on both long-term depression and PPD were eliminated by treatment with an mGluR1-selective antagonist. These findings suggest that variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes implicated in glutamatergic synaptic signaling.
HubMed – depression

Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception.

Filed under: Depression Treatment

Proc Natl Acad Sci U S A. 2012 Oct 8;
Weikum WM, Oberlander TF, Hensch TK, Werker JF

Language acquisition reflects a complex interplay between biology and early experience. Psychotropic medication exposure has been shown to alter neural plasticity and shift sensitive periods in perceptual development. Notably, serotonin reuptake inhibitors (SRIs) are antidepressant agents increasingly prescribed to manage antenatal mood disorders, and depressed maternal mood per se during pregnancy impacts infant behavior, also raising concerns about long-term consequences following such developmental exposure. We studied whether infants’ language development is altered by prenatal exposure to SRIs and whether such effects differ from exposure to maternal mood disturbances. Infants from non-SRI-treated mothers with little or no depression (control), depressed but non-SRI-treated (depressed-only), and depressed and treated with an SRI (SRI-exposed) were studied at 36 wk gestation (while still in utero) on a consonant and vowel discrimination task and at 6 and 10 mo of age on a nonnative speech and visual language discrimination task. Whereas the control infants responded as expected (success at 6 mo and failure at 10 mo) the SRI-exposed infants failed to discriminate the language differences at either age and the depressed-only infants succeeded at 10 mo instead of 6 mo. Fetuses at 36 wk gestation in the control condition performed as expected, with a response on vowel but not consonant discrimination, whereas the SRI-exposed fetuses showed accelerated perceptual development by discriminating both vowels and consonants. Thus, prenatal depressed maternal mood and SRI exposure were found to shift developmental milestones bidirectionally on infant speech perception tasks.
HubMed – depression

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