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. 2019 Aug 27;11(9):2014.
doi: 10.3390/nu11092014.

Maternal Creatine Supplementation Positively Affects Male Rat Hippocampal Synaptic Plasticity in Adult Offspring

Stefano Sartini  1 , Davide Lattanzi  2 , Michael Di Palma  2 , David Savelli  2 , Silvia Eusebi  2 , Piero Sestili  2 , Riccardo Cuppini  2 , Patrizia Ambrogini  2
Affiliations

Maternal Creatine Supplementation Positively Affects Male Rat Hippocampal Synaptic Plasticity in Adult Offspring

Stefano Sartini et al. Nutrients. .

Abstract

Creatine plays a crucial role in developing the brain, so much that its genetic deficiency results in mental dysfunction and cognitive impairments. Moreover, creatine supplementation is currently under investigation as a preventive measure to protect the fetus against oxidative stress during difficult pregnancies. Although creatine use is considered safe, posing minimal risk to clinical health, we found an alteration in morpho-functional maturation of neurons when male rats were exposed to creatine loads during brain development. In particular, increased excitability and enhanced long-term potentiation (LTP) were observed in the hippocampal pyramidal neurons of weaning pups. Since these effects were observed a long time after creatine treatment had been terminated, long-lasting modifications persisting into adulthood were hypothesized. Such modifications were investigated in the present study using morphological, electrophysiological, and calcium imaging techniques applied to hippocampal Cornu Ammonis 1 (CA1) neurons of adult rats born from dams supplemented with creatine. When compared to age-matched controls, the treated adult offspring were found to retain enhanced neuron excitability and an improved LTP, the best-documented neuronal substrate for memory formation. While translating data from rats to humans does have limitations, our findings suggest that prenatal creatine supplementation could have positive effects on adult cognitive abilities.

Keywords: adult offspring; creatine supplementation; hippocampus; long-term potentiation; neuron excitability; prenatal treatment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of maternal creatine supplementation on basal synaptic transmission and long-term potentiation (LTP) in adult Cornu Ammonis 1 (CA1) neurons. (A) High-frequency stimulation of Schaffer collaterals results in a more pronounced LTP in treated CA1 neurons. The field excitatory postsynaptic potential (fEPSP) slope (between 10% and 80% of max) was analyzed as a measure of synaptic strength; values were normalized to the mean value obtained over the last 15 min of the baseline period and expressed as a percentage of this baseline value. Two-way ANOVA with Time and Treatment (CTRL vs TREAT) as independent variables while the litter was considered as a blocking factor; Time: F (1, 2692) = 861.69 p < 0.001, Treatment: F (1, 2692) = 103.24 p < 0.001, Time-by-Treatment Interaction: F (1, 2692) = 117.33 p < 0.001 (control, CTRL: n = 11 slices; treated, TREAT: n = 16 slices). (B) Input/output curves for treated and control rats were measured by plotting fEPSP slopes and their corresponding presynaptic fiber volley amplitudes at increasing stimulus intensities. Basal synaptic transmission is altered in treated (n = 17 slices) rats compared to controls (n = 18 slices). Linear regression p = 0.0011. CTRL = 5 rats; TREAT = 5 rats.
Figure 2
Figure 2
Creatine maternal supplementation affects input resistance in adult CA1 neurons. Neurons of treated rats excited by current injections above 150 pA do not show differences in input resistance compared to treated neurons excited by current injections below 150 pA, while such differences were found in neurons of control rats. Two-way ANOVA with Intensity of stimulation and Treatment (CTRL vs TREAT) as independent variables while the litter was considered as a blocking factor; Intensity: F (1, 42) = 14.69 p = 0.0004; >150 pA CTRL: n=11 neurons; TREAT: n = 11 neurons; <150 pA CTRL: n = 14 neurons; TREAT: n = 11 neurons. Sidak’s multiple comparisons test: <150 pA CTRL vs. >150 pA CTRL * p = 0.0116. CTRL = 5 rats; TREAT = 5 rats.
Figure 3
Figure 3
Creatine prenatal treatment effects on CA1 pyramidal cell excitability in adult progeny. (A) Neurons of treated rats show lower action potential amplitude than control neurons. Unpaired t-test * p = 0.033; CTRL = 25 neurons; TREAT = 25 neurons. (B) Current-clamp recording of action potentials generated by direct intracellular injections of depolarizing current (bringing the membrane potential from approximately −70 to −10mV). An afterhyperpolarization is observable following action potential burst. (C) Creatine supplementation reduces the afterhyperpolarization appearance in CA1 neurons. CTRL = 25 neurons; TREAT = 25 neurons. Fisher’s exact test: * p = 0.012. CTRL = 5 rats; TREAT = 5 rats.
Figure 4
Figure 4
Morphological analysis of biocytin-stained neurons from the CA1 region of the hippocampus. Creatine maternal supplementation does not affect neuronal morphology in adult progeny. (A) Dendritic length of the CA1 pyramidal cells. (B) Scholl analysis plot showing numbers of dendritic crossings along the Scholl rings as a function of distance from the soma. Distributions of both basal and apical dendritic crossings do not result in significant differences between the two groups, two-way ANOVA with Distance from soma and Treatment (CTRL vs. TREAT) as independent variables while the litter was considered as a blocking factor; CTRL: n = 16 neurons; TREAT: n = 13 neurons. CTRL = 5 rats; TREAT = 5 rats.
Figure 5
Figure 5
Intracellular somatic calcium transients. (A) Calcium transients evoked by single action potentials; (B) calcium transients evoked by 300 ms-20 Hz action potentials burst. Creatine maternal supplementation significantly decreases calcium influx during 20 Hz action potential burst in CA1 neurons. Two-way ANOVA with Time and Treatment (CTRL vs. TREAT) as independent variables while the litter was considered as a blocking factor; Time: F (1, 645) = 305.47 p < 0.001, Treatment: F (1, 645) = 51.74 p < 0.001, Time-by-Treatment Interaction: F (1, 645) = 19.02 p < 0.001. Sidak’s multiple comparisons test: p < 0.05 from 4.9 to 5.6 s. CTRL = 8 neurons from 5 rats; TREAT = 5 neurons from 4 rats.
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