Brain-Generated 17ß-Estradiol Modulates Long-Term Synaptic Plasticity in the Primary Auditory Cortex of Adult Male Rats.

Neuron-derived 17ß-estradiol (E2) alters synaptic transmission and plasticity in brain regions with endocrine and non-endocrine functions. Investigations into a modulatory role of E2 in synaptic activity and plasticity have mainly focused on the rodent hippocampal formation. In songbirds, E2 is synthesized by auditory forebrain neurons and promotes auditory signal processing and memory for salient acoustic stimuli; however, the modulatory effects of E2 on memory-related synaptic plasticity mechanisms have not been directly examined in the auditory forebrain. We investigated the effects of bidirectional E2 manipulations on synaptic transmission and long-term potentiation (LTP) in the rat primary auditory cortex (A1). Immunohistochemistry revealed widespread neuronal expression of the E2 biosynthetic enzyme aromatase in multiple regions of the rat sensory and association neocortex, including A1. In A1, E2 application reduced the threshold for in vivo LTP induction at layer IV synapses, whereas pharmacological suppression of E2 production by aromatase inhibition abolished LTP induction at layer II/III synapses. In acute A1 slices, glutamate and γ-aminobutyric acid (GABA) receptor-mediated currents were sensitive to E2 manipulations in a layer-specific manner. These findings demonstrate that locally synthesized E2 modulates synaptic transmission and plasticity in A1 and suggest potential mechanisms by which E2 contributes to auditory signal processing and memory.

Effects of Patterned Sound Deprivation on Short- and Long-Term Plasticity in the Rat Thalamocortical Auditory System In Vivo.

Postnatal sensory experience plays a significant role in the maturation and synaptic stabilization of sensory cortices, such as the primary auditory cortex (A1). Here, we examined the effects of patterned sound deprivation (by rearing in continuous white noise, WN) during early postnatal life on short- and long-term plasticity of adult male rats using an in vivo preparation (urethane anesthesia). Relative to age-matched control animals reared under unaltered sound conditions, rats raised in WN (from postnatal day 5 to 50-60) showed greater levels of long-term potentiation (LTP) of field potentials in A1 induced by theta-burst stimulation (TBS) of the medial geniculate nucleus (MGN). In contrast, analyses of short-term plasticity using paired-pulse stimulation (interstimulus intervals of 25-1000 ms) did not reveal any significant effects of WN rearing. However, LTP induction resulted in a significant enhancement of paired-pulse depression (PPD) for both rearing conditions. We conclude that patterned sound deprivation during early postnatal life results in the maintenance of heightened, juvenile-like long-term plasticity (LTP) into adulthood. Further, the enhanced PPD following LTP induction provides novel evidence that presynaptic mechanisms contribute to thalamocortical LTP in A1 under in vivo conditions.

Is hippocampal theta frequency related to individual and sex differences in anxiety-like behaviour? An analysis in male and female Long-Evans rats.

Hippocampal theta activity is a prominent slow (4-12 Hz) oscillatory activity pattern generated in the mammalian hippocampal formation. Based on evidence that anxiolytic drugs consistently decrease the frequency of hippocampal theta activity in rodents, hippocampal theta has been linked to anxiety states, leading to the influential theta suppression model of anxiolysis. Surprisingly, very few studies have examined whether hippocampal theta frequency relates to individual or sex differences in anxiety-like behaviour. Here, male and female rats were tested on the elevated plus maze (EPM) to quantify levels of defensive, anxiety-like behaviours. Females exhibited higher levels of open arm exploration (open arm entries and open arm time) compared to males, suggestive of reduced anxiety in females. Subsequently, reticular-elicited hippocampal theta activity was characterized in the same rats under deep urethane anesthesia. There was no sex difference in theta frequency over a range of stimulation intensities. Further, there were no significant correlations between behavioural measures of anxiety in the EPM and theta frequency among individual animals. Theta frequency did, however, decrease following systemic administration of the clinically-used anxiolytic agent buspirone (10 mg/kg). Together, these results suggest that theta frequency does not relate to levels of anxiety-like behaviours in the EPM in male and female rats, challenging the predictive validity of hippocampal theta activity as an index of anxiety in rodents.

Gating of long-term potentiation (LTP) in the thalamocortical auditory system of rats by serotonergic (5-HT) receptors.

The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) plays an important role in controlling the induction threshold and maintenance of long-term potentiation (LTP) in the visual cortex and hippocampus of rodents. Serotonergic fibers also innervate the rodent primary auditory cortex (A1), but the regulation of A1 plasticity by 5-HT receptors (5-HTRs) is largely uncharted. Thus, we examined the role of several, predominant 5-HT receptor classes (5-HT1ARs, 5-HT2Rs, and 5-HT3Rs) in gating in vivo LTP induction at A1 synapses of adult, urethane-anesthetized rats. Theta-burst stimulation (TBS) applied to the medial geniculate nucleus resulted in successful LTP induction of field postsynaptic potentials (fPSPs) generated by excitation of thalamocortical and intracortical A1 synapses. Local application (by reverse microdialysis in A1) of the broad-acting 5-HTR antagonist methiothepin suppressed LTP at both thalamocortical and intracortical synapses. In fact, rather than LTP, TBS elicited long-term depression during methiothepin application, an effect that was mimicked by the selective 5-HT2R antagonist ketanserin, but not the 5-HT1AR blocker WAY 100635. Interestingly, antagonism of 5-HT3Rs by granisetron selectively blocked LTP at thalamocortical, but not intracortical A1 synapses. Further, in the absence of TBS, granisetron application resulted in a pronounced increase in fPSP amplitude, suggesting that 5-HT3Rs play an important role in regulating baseline (non-potentiated) transmission at A1 synapses. Together, these results indicate that activation of 5-HT2Rs and 5-HT3Rs, but not 5-HT1ARs, exerts a clear, facilitating effect on LTP induction at A1 synapses, allowing 5-HT to act as a powerful regulator of long-term plasticity induction in the fully matured A1 of mammalian species.