Presynaptic GABAB receptor–mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice

Abstract

The TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor–mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen. Graphical abstract

Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism

“…The alteration in the balance between inhibitory and excitatory synaptic transmission is emerging as a fundamental principle underlying a variety of neuropsychiatric and neurodevelopmental disorders, such as ASD and epilepsy. Using the ratio of mEPSCs over mIPSCs to describe the change of E/I balance is a common method ( Bassetti et al, 2021 ; Huang et al, 2021 ). It can show the whole view of the excitatory synaptic inputs and inhibitory synaptic inputs from the postsynaptic neuron.…”

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

“…Regarding EPSCs, we observed that while there was a non-significant trend towards increased EPSC frequency during NA wash in for both groups (Figure 4G), no statistically significant differences could be found between the two EGFP-shRNA-expressing groups (Figure 4G-H). Based on these results, we plotted the ratio of EPSC over IPSC frequencies during baseline, NA wash in and NA wash out (Figure 5A) to estimate an E/I ratio (Zhou et al, 2009;Bassetti et al, 2021;Kirischuk, 2022). This plot highlights that in the Adra1a-shRNA group, there is an imbalance in favor of excitation, when the circuit is either in its basal state, or following the wash out of NA from the recording bath.…”

Distinct neuronal excitability alterations of medial prefrontal cortex in early‐life neglect model of rats

“…Regarding the E/I ratio, the results were similar, but by different implementation: male rats by more excited glutamatergic neurons, female rats by less excited GABAergic neurons. In the future, the exact E/I ratio can be examined by ratio of (m/s) EPSC frequency to (m/s) IPSC frequency 22 …”

“…In the future, the exact E/I ratio can be examined by ratio of (m/s) EPSC frequency to (m/s) IPSC frequency. 22 Sex differences in the nervous system due to estrous cycle, sex hormones, and their receptors have gained increasing attention in recent years. 23 Yousuf et al demonstrated that infralimbic estradiol could enhance neuronal excitability of female rats, 24 which could be a putative reason for the sexually dimorphic effects.…”